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Research Article

IL-2-mediated hepatotoxicity: knowledge gap identification based on the irAOP concept

Luise A. Rosera Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Frankfurt am Main, GermanyCorrespondence[email protected]
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Christina Sakellarioub Department of Immunotechnology, Lund University, Lund, SwedenView further author information
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Malin Lindstedtb Department of Immunotechnology, Lund University, Lund, SwedenORCID Iconhttps://orcid.org/0000-0001-9136-1087View further author information
ORCID Icon,
Vanessa Neuhausc Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Preclinical Pharmacology and In-Vitro Toxicology, Hannover, Germany;d Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hannover, GermanyView further author information
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Susann Dehmelc Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Preclinical Pharmacology and In-Vitro Toxicology, Hannover, Germany;d Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hannover, GermanyView further author information
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Charline Sommerc Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Preclinical Pharmacology and In-Vitro Toxicology, Hannover, Germany;d Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hannover, GermanyView further author information
,
Martin Raasche Dynamic42 GmbH, Jena, GermanyView further author information
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Thierry Flandref Translational Medicine, Novartis Institutes of Biomedical Research, Basel, SwitzerlandView further author information
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Sigrid Roesenerg Chemical and Preclinical Safety, Merck Healthcare KGaA, Darmstadt, GermanyView further author information
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Philip Hewittg Chemical and Preclinical Safety, Merck Healthcare KGaA, Darmstadt, GermanyView further author information
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Michael J. Parnhama Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Frankfurt am Main, Germany;h EpiEndo Pharmaceuticals ehf, Reykjavík, IcelandView further author information
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Katherina Sewaldc Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Preclinical Pharmacology and In-Vitro Toxicology, Hannover, Germany;d Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hannover, GermanyView further author information
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Susanne Schiffmannh EpiEndo Pharmaceuticals ehf, Reykjavík, IcelandORCID Iconhttps://orcid.org/0000-0001-5035-2504View further author information
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Article: 2332177 | Received 10 Jul 2023, Accepted 13 Mar 2024, Published online: 05 Apr 2024

References

  • Abbas AK, Trotta E, R Simeonov D, Marson A, Bluestone JA. 2018. Revisiting IL-2: biology and therapeutic prospects. Sci Immunol. 3(25):eaat1482. doi:10.1126/sciimmunol.aat1482.
  • Abdel-Salam BK, Ebaid H. 2014. Expression of CD11b and CD18 on polymorphonuclear neutrophils stimulated with interleukin-2. Cent Eur J Immunol. 39(2):209–215. doi:10.5114/ceji.2014.43725.
  • Allavena P, Bianchi G, Zhou D, van Damme J, Jílek P, Sozzani S, Mantovani A. 1994. Induction of natural killer cell migration by monocyte chemotactic protein − 1, −2 and −3. Eur J Immunol. 24(12):3233–3236. doi:10.1002/eji.1830241249.
  • Anderson JA, Lentsch AB, Hadjiminas DJ, Miller FN, Martin AW, Nakagawa K, Edwards MJ. 1996. The role of cytokines, adhesion molecules, and chemokines in interleukin-2-induced lymphocytic infiltration in C57BL/6 mice. J Clin Invest. 97(8):1952–1959. doi:10.1172/JCI118627.
  • Ando K, Hiroishi K, Kaneko T, Moriyama T, Muto Y, Kayagaki N, Yagita H, Okumura K, Imawari M. 1997. Perforin, Fas/Fas ligand, and TNF-alpha pathways as specific and bystander killing mechanisms of hepatitis C virus-specific human CTL. J Immunol. 158(11):5283–5291.
  • Ankley GT, Bennett RS, Erickson RJ, Hoff DJ, Hornung MW, Johnson RD, Mount DR, Nichols JW, Russom CL, Schmieder PK, et al. 2010. Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem. 29(3):730–741. doi:10.1002/etc.34.
  • Aoki CA, Roifman CM, Lian Z-X, Bowlus CL, Norman GL, Shoenfeld Y, Mackay IR, Gershwin ME. 2006. IL-2 receptor alpha deficiency and features of primary biliary cirrhosis. J Autoimmun. 27(1):50–53. doi:10.1016/j.jaut.2006.04.005.
  • Armant M, Delespesse G, Sarfati M. 1995. IL-2 and IL-7 but not IL-12 protect natural killer cells from death by apoptosis and up-regulate bcl-2 expression. Immunology. 85(2):331–337.
  • Aronson FR, Libby P, Brandon EP, Janicka MW, Mier JW. 1988. IL-2 rapidly induces natural killer cell adhesion to human endothelial cells. A potential mechanism for endothelial injury. J Immunol. 141(1):158–163. doi:10.4049/jimmunol.141.1.158.
  • Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, et al. 1999. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 17(7):2105–2116. doi:10.1200/JCO.1999.17.7.2105.
  • Au-Yeung B, Smith GA, Mueller JL, Heyn CS, Jaszczak RG, Weiss A, Zikherman J. 2017. IL-2 modulates the TCR signaling threshold for CD8 but not CD4 T cell proliferation on a single cell level. J Immunol. 198(6):2445–2456. doi:10.4049/jimmunol.1601453.
  • Babai S, Auclert L, Le-Louët H. 2021. Safety data and withdrawal of hepatotoxic drugs. Therapie. 76(6):715–723. doi:10.1016/j.therap.2018.02.004.
  • Baev DV, Peng X-H, Song L, Barnhart JR, Crooks GM, Weinberg KI, Metelitsa LS. 2004. Distinct homeostatic requirements of CD4+ and CD4- subsets of Valpha24-invariant natural killer T cells in humans. Blood. 104(13):4150–4156. doi:10.1182/blood-2004-04-1629.
  • Ball T, Barber CG, Cayley A, Chilton ML, Foster R, Fowkes A, Heghes C, Hill E, Hill N, Kane S, et al. 2021. Beyond adverse outcome pathways: making toxicity predictions from event networks, SAR models, data and knowledge. Toxicol Res. 10(1):102–122. doi:10.1093/toxres/tfaa099.
  • Bal-Price A, Meek MEB. 2017. Adverse outcome pathways: application to enhance mechanistic understanding of neurotoxicity. Pharmacol Ther. 179:84–95. doi:10.1016/j.pharmthera.2017.05.006.
  • Bandyopadhyay K, Marrero I, Kumar V. 2016. NKT cell subsets as key participants in liver physiology and pathology. Cell Mol Immunol. 13(3):337–346. doi:10.1038/cmi.2015.115.
  • Barbier L, Ferhat M, Salamé E, Robin A, Herbelin A, Gombert J-M, Silvain C, Barbarin A. 2019. Interleukin-1 family cytokines: keystones in liver inflammatory diseases. Front Immunol. 10:2014. doi:10.3389/fimmu.2019.02014.
  • Baume DM, Robertson MJ, Levine H, Manley TJ, Schow PW, Ritz J. 1992. Differential responses to interleukin 2 define functionally distinct subsets of human natural killer cells. Eur J Immunol. 22(1):1–6. doi:10.1002/eji.1830220102.
  • Behfarjam F, Sanati MH, Nasseri Moghaddam S, Ataei M, Nikfam S, Jadali Z. 2017. Role of Th1/Th2 cells and related cytokines in autoimmune hepatitis. Turk J Gastroenterol. 28(2):110–114. doi:10.5152/tjg.2017.17501.
  • Belaid B, Lamara Mahammed L, Mohand Oussaid A, Migaud M, Khadri Y, Casanova JL, Puel A, Ben Halla N, Djidjik R. 2021. Case report: interleukin-2 receptor common gamma chain defect presented as a hyper-IgE syndrome. Front Immunol. 12:696350. doi:10.3389/fimmu.2021.696350.
  • Benczik M, Gaffen SL. 2004. The interleukin (IL)-2 family cytokines: survival and proliferation signaling pathways in T lymphocytes. Immunol Invest. 33(2):109–142. doi:10.1081/imm-120030732.
  • Bénéchet AP, Simone G d, Di Lucia P, Cilenti F, Barbiera G, Le Bert N, Fumagalli V, Lusito E, Moalli F, Bianchessi V, et al. 2019. Dynamics and genomic landscape of CD8+ T cells undergoing hepatic priming. Nature. 574(7777):200–205. doi:10.1038/s41586-019-1620-6.
  • Bessoles S, Fouret F, Dudal S, Besra GS, Sanchez F, Lafont V. 2008. IL‐2 triggers specific signaling pathways in human NKT cells leading to the production of pro‐ and anti‐inflammatory cytokines. J Leukoc Biol. 84(1):224–233. doi:10.1189/jlb.1007669.
  • Bethesda. 2018. Aldesleukin: liverTox: clinical and research information on drug-induced liver injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases.
  • Beyer T, Busse M, Hristov K, Gurbiel S, Smida M, Haus U-U, Ballerstein K, Pfeuffer F, Weismantel R, Schraven B, et al. 2011. Integrating signals from the T-cell receptor and the interleukin-2 receptor. PLoS Comput Biol. 7(8):e1002121. doi:10.1371/journal.pcbi.1002121.
  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. 2013. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 144(7):1419–1425.e3. doi:10.1053/j.gastro.2013.02.006.
  • Blachère NE, Morris HK, Braun D, Saklani H, Di Santo JP, Darnell RB, Albert ML. 2006. IL-2 is required for the activation of memory CD8+ T cells via antigen cross-presentation. J Immunol. 176(12):7288–7300. doi:10.4049/jimmunol.176.12.7288.
  • Blaurock-Möller N, Gröger M, Siwczak F, Dinger J, Schmerler D, Mosig AS, Kiehntopf M. 2019. CAAP48, a new sepsis biomarker, induces hepatic dysfunction in an in vitro liver-on-chip model. Front Immunol. 10:273. doi:10.3389/fimmu.2019.00273.
  • Bode JG, Albrecht U, Häussinger D, Heinrich PC, Schaper F. 2012. Hepatic acute phase proteins–regulation by IL-6- and IL-1-type cytokines involving STAT3 and its crosstalk with NF-κB-dependent signaling. Eur J Cell Biol. 91(6-7):496–505. doi:10.1016/j.ejcb.2011.09.008.
  • Bonder CS, Norman MU, Swain MG, Zbytnuik LD, Yamanouchi J, Santamaria P, Ajuebor M, Salmi M, Jalkanen S, Kubes P. 2005. Rules of recruitment for Th1 and Th2 lymphocytes in inflamed liver: a role for alpha-4 integrin and vascular adhesion protein-1. Immunity. 23(2):153–163. doi:10.1016/j.immuni.2005.06.007.
  • Bonnema JD, Rivlin KA, Ting AT, Schoon RA, Abraham RT, Leibson PJ. 1994. Cytokine-enhanced NK cell-mediated cytotoxicity. Positive modulatory effects of IL-2 and IL-12 on stimulus-dependent granule exocytosis. J Immunol. 152(5):2098–2104.
  • Bosco MC, Curiel RE, Zea AH, Malabarba MG, Ortaldo JR, Espinoza-Delgado I. 2000. IL-2 signaling in human monocytes involves the phosphorylation and activation of p59hck. J Immunol. 164(9):4575–4585. doi:10.4049/jimmunol.164.9.4575.
  • Bosco MC, Espinoza-Delgado I, Schwabe M, Gusella GL, Longo DL, Sugamura K, Varesio L. 1994a. Regulation by interleukin-2 (IL-2) and interferon gamma of IL-2 receptor gamma chain gene expression in human monocytes. Blood. 83(10):2995–3002. doi:10.1182/blood.V83.10.2995.2995.
  • Bosco MC, Espinoza-Delgado I, Schwabe M, Russell SM, Leonard WJ, Longo DL, Varesio L. 1994b. The gamma subunit of the interleukin-2 receptor is expressed in human monocytes and modulated by interleukin-2, interferon gamma, and transforming growth factor beta 1. Blood. 83(12):3462–3467. doi:10.1182/blood.V83.12.3462.bloodjournal83123462.
  • Boyman O, Sprent J. 2012. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol. 12(3):180–190. doi:10.1038/nri3156.
  • Boyman O, Surh CD, Sprent J. 2006. Potential use of IL-2/anti-IL-2 antibody immune complexes for the treatment of cancer and autoimmune disease. Expert Opin Biol Ther. 6(12):1323–1331. doi:10.1517/14712598.6.12.1323.
  • Burton J, Goldman CK, Rao P, Moos M, Waldmann TA. 1990. Association of intercellular adhesion molecule 1 with the multichain high-affinity interleukin 2 receptor. Proc Natl Acad Sci U S A. 87(18):7329–7333. doi:10.1073/pnas.87.18.7329.
  • Cabrera R, Ararat M, Cao M, Xu Y, Wasserfall C, Atkinson MA, Liu C, Nelson DR. 2010a. Hepatocellular carcinoma immunopathogenesis: clinical evidence for global T cell defects and an immunomodulatory role for soluble CD25 (sCD25). Dig Dis Sci. 55(2):484–495. doi:10.1007/s10620-009-0955-5.
  • Cabrera R, Ararat M, Eksioglu EA, Cao M, Xu Y, Wasserfall C, Atkinson MA, Liu C, Nelson DR. 2010b. Influence of serum and soluble CD25 (sCD25) on regulatory and effector T-cell function in hepatocellular carcinoma. Scand J Immunol. 72(4):293–301. doi:10.1111/j.1365-3083.2010.02427.x.
  • Castell JV, Gómez-Lechón MJ, David M, Andus T, Geiger T, Trullenque R, Fabra R, Heinrich PC. 1989. Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes. FEBS Lett. 242(2):237–239. doi:10.1016/0014-5793(89)80476-4.
  • Chung CS, Yang S, Song GY, Lomas J, Wang P, Simms HH, Chaudry IH, Ayala A. 2001. Inhibition of Fas signaling prevents hepatic injury and improves organ blood flow during sepsis. Surgery. 130(2):339–345. doi:10.1067/msy.2001.116540.
  • Crispe IN, Dao T, Klugewitz K, Mehal WZ, Metz DP. 2000. The liver as a site of T-cell apoptosis: graveyard, or killing field? Immunol Rev. 174(1):47–62. doi:10.1034/j.1600-0528.2002.017412.x.
  • Crispe IN. 2003. Hepatic T cells and liver tolerance. Nat Rev Immunol. 3(1):51–62. doi:10.1038/nri981.
  • Curran RD, Billiar TR, West MA, Bentz BG, Simmons RL. 1988. Effect of interleukin 2 on Kupffer cell activation. Interleukin 2 primes and activates Kupffer cells to suppress hepatocyte protein synthesis in vitro. Arch Surg. 123(11):1373–1378. doi:10.1001/archsurg.1988.01400350087013.
  • David D, Bani L, Moreau J-L, Demaison C, Sun K, Salvucci O, Nakarai T, Montalembert M d, Chouaı¨b S, Joussemet M, et al. 1998. Further analysis of interleukin-2 receptor subunit expression on the different human peripheral blood mononuclear cell subsets. Blood. 91(1):165–172. doi:10.1182/blood.V91.1.165.165_165_172.
  • David S, Hamilton JP. 2010. Drug-induced liver injury. US Gastroenterol Hepatol Rev. 6:73–80.
  • de Jong LM, Jiskoot W, Swen JJ, Manson ML. 2020. Distinct effects of inflammation on cytochrome P450 regulation and drug metabolism: lessons from experimental models and a potential role for pharmacogenetics. Genes. 11(12):1509. doi:10.3390/genes11121509.
  • DeLeve LD, Maretti-Mira AC. 2017. Liver sinusoidal endothelial cell: an update. Semin Liver Dis. 37(4):377–387. doi:10.1055/s-0037-1617455.
  • Diehl L, Schurich A, Grochtmann R, Hegenbarth S, Chen L, Knolle PA. 2008. Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance. Hepatology. 47(1):296–305. doi:10.1002/hep.21965.
  • Djeu JY, Liu JH, Wei S, Rui H, Pearson CA, Leonard WJ, Blanchard DK. 1993. Function associated with IL-2 receptor-beta on human neutrophils. Mechanism of activation of antifungal activity against Candida albicans by IL-2. J Immunol. 150(3):960–970. doi:10.4049/jimmunol.150.3.960.
  • Downie GH, Ryan US, Hayes BA, Friedman M. 1992. Interleukin-2 directly increases albumin permeability of bovine and human vascular endothelium in vitro. Am J Respir Cell Mol Biol. 7(1):58–65. doi:10.1165/ajrcmb/7.1.58.
  • D'Souza WN, Lefrançois L. 2003. IL-2 is not required for the initiation of CD8 T cell cycling but sustains expansion. J Immunol. 171(11):5727–5735. doi:10.4049/jimmunol.171.11.5727.
  • D'Souza WN, Schluns KS, Masopust D, Lefrançois L. 2002. Essential role for IL-2 in the Regulation of antiviral extralymphoid CD8 T cell responses. J Immunol. 168(11):5566–5572. doi:10.4049/jimmunol.168.11.5566.
  • Du Y, Li N, Yang H, Luo C, Gong Y, Tong C, Gao Y, Lü S, Long M. 2017. Mimicking liver sinusoidal structures and functions using a 3D-configured microfluidic chip. Lab Chip. 17(5):782–794. doi:10.1039/c6lc01374k.
  • Dutcher J, Atkins MB, Margolin K, Weiss G, Clark J, Sosman J, Logan T, Aronson F, Mier J. 2001. Kidney cancer: the cytokine working group experience (1986–2001). Med Oncol. 18(3):209–219. doi:10.1385/MO:18:3:209.
  • Dutcher JP, Schwartzentruber DJ, Kaufman HL, Agarwala SS, Tarhini AA, Lowder JN, Atkins MB. 2014. High dose interleukin-2 (Aldesleukin) - expert consensus on best management practices-2014. J Immunother Cancer. 2(1):26. doi:10.1186/s40425-014-0026-0.
  • Eksteen B, Miles A, Curbishley SM, Tselepis C, Grant AJ, Walker LSK, Adams DH. 2006. Epithelial inflammation is associated with CCL28 production and the recruitment of regulatory T cells expressing CCR10. J Immunol. 177(1):593–603. doi:10.4049/jimmunol.177.1.593.
  • Emoto M, Mittrücker HW, Schmits R, Mak TW, Kaufmann SH. 1999. Critical role of leukocyte function-associated antigen-1 in liver accumulation of CD4 + NKT cells. J Immunol. 162(9):5094–5098.
  • Espinoza‐Delgado I, Bosco MC, Musso T, Gusella GL, Longo DL, Varesio L. 1995. Interleukin‐2 and human monocyte activation. J Leukoc Biol. 57(1):13–19. doi:10.1002/jlb.57.1.13.
  • Espinoza‐Delgado I, Longo D, Gusella G, Varesio L. 1992. Regulation of IL-2 receptor subunit genes in human monocytes. Differential effects of IL-2 and IFN-gamma. J Immunol. 149(9):2961–2968.
  • Espinoza-Delgado I, Longo DL, Gusella GL, Varesio L. 1990. IL-2 enhances c-fms expression in human monocytes. J Immunol. 145(4):1137–1143.
  • Esser MT, Dinglasan RD, Krishnamurthy B, Gullo CA, Graham MB, Braciale VL. 1997. IL-2 induces Fas ligand/Fas (CD95L/CD95) cytotoxicity in CD8+ and CD4+ T lymphocyte clones. J Immunol. 158(12):5612–5618.
  • Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, Habuka M, Tahmasebpoor S, Danielsson A, Edlund K, et al. 2013. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics*. Mol Cell Proteomics. 13(2):397–406. doi:10.1074/mcp.M113.035600.
  • Fisher B, Keenan AM, Garra BS, Steinberg SM, White DE, DiBisceglie AM, Hoofnagle JH, Yolles P, Rosenberg SA, Lotze MT. 1989. Interleukin-2 induces profound reversible cholestasis: a detailed analysis in treated cancer patients. J Clin Oncol. 7(12):1852–1862. doi:10.1200/JCO.1989.7.12.1852.
  • Fontana RJ. 2014. Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives. Gastroenterology. 146(4):914–928. doi:10.1053/j.gastro.2013.12.032.
  • Francis P, Navarro VJ. 2022. Drug induced hepatotoxicity. St. Petersburg (FL): StatPearls Publishing.
  • French JB, Bonacini M, Ghabril M, Foureau D, Bonkovsky HL. 2016. Hepatotoxicity associated with the use of anti-TNF-α agents. Drug Saf. 39(3):199–208. doi:10.1007/s40264-015-0366-9.
  • Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. 1995. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 13(3):688–696. doi:10.1200/JCO.1995.13.3.688.
  • Gantner F, Leist M, Küsters S, Vogt K, Volk HD, Tiegs G. 1996. T cell stimulus-induced crosstalk between lymphocytes and liver macrophages results in augmented cytokine release. Exp Cell Res. 229(1):137–146. doi:10.1006/excr.1996.0351.
  • Gao B, Radaeva S, Park O. 2009. Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases. J Leukoc Biol. 86(3):513–528. doi:10.1189/jlb.0309135.
  • Geissmann F, Cameron TO, Sidobre S, Manlongat N, Kronenberg M, Briskin MJ, Dustin ML, Littman DR. 2005. Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids. PLoS Biol. 3(4):e113. doi:10.1371/journal.pbio.0030113.
  • Gerussi A, Natalini A, Antonangeli F, Mancuso C, Agostinetto E, Barisani D, Di Rosa F, Andrade R, Invernizzi P. 2021. Immune-mediated drug-induced liver injury: immunogenetics and experimental models. Int J Mol Sci. 22(9):4557. doi:10.3390/ijms22094557.
  • Gijbels E, Vinken M. 2017. An update on adverse outcome pathways leading to liver injury. Appl in Vitro Toxicol. 3(4):283–285. doi:10.1089/aivt.2017.0027.
  • Girard D, Gosselin J, Heitz D, Paquin R, Beaulieu AD. 1995. Effects of interleukin-2 on gene expression in human neutrophils. Blood. 86(3):1170–1176.
  • Goebel J, Forrest K, Morford L, Roszman TL. 2002. Differential localization of IL-2- and -15 receptor chains in membrane rafts of human T cells. Journal of Leukocyte Biology. 72(1):199–206. doi:10.1189/jlb.72.1.199.
  • Grant AJ, Roessler E, Ju G, Tsudo M, Sugamura K, Waldmann TA. 1992. The interleukin 2 receptor (IL-2R): the IL-2R alpha subunit alters the function of the IL-2R beta subunit to enhance IL-2 binding and signaling by mechanisms that do not require binding of IL-2 to IL-2R alpha subunit. Proc Natl Acad Sci U S A. 89(6):2165–2169. doi:10.1073/pnas.89.6.2165.
  • Grivennikov SI, Tumanov AV, Liepinsh DJ, Kruglov AA, Marakusha BI, Shakhov AN, Murakami T, Drutskaya LN, Förster I, Clausen BE, et al. 2005. Distinct and nonredundant in vivo functions of TNF produced by t cells and macrophages/neutrophils: protective and deleterious effects. Immunity. 22(1):93–104. doi:10.1016/j.immuni.2004.11.016.
  • Guidotti LG, Iannacone M. 2013. Effector CD8 T cell trafficking within the liver. Mol Immunol. 55(1):94–99. doi:10.1016/j.molimm.2012.10.032.
  • Guidotti LG, Inverso D, Sironi L, Di Lucia P, Fioravanti J, Ganzer L, Fiocchi A, Vacca M, Aiolfi R, Sammicheli S, et al. 2015. Immunosurveillance of the liver by intravascular effector CD8(+) T cells. Cell. 161(3):486–500. doi:10.1016/j.cell.2015.03.005.
  • Heesch K, Raczkowski F, Schumacher V, Hünemörder S, Panzer U, Mittrücker H-W. 2014. The function of the chemokine receptor CXCR6 in the T cell response of mice against Listeria monocytogenes. PLoS One. 9(5):e97701. doi:10.1371/journal.pone.0097701.
  • Hémar A, Subtil A, Lieb M, Morelon E, Hellio R, Dautry-Varsat A. 1995. Endocytosis of interleukin 2 receptors in human T lymphocytes: distinct intracellular localization and fate of the receptor alpha, beta, and gamma chains. J Cell Biol. 129(1):55–64. doi:10.1083/jcb.129.1.55.
  • Heymann F, Tacke F. 2016. Immunology in the liver–from homeostasis to disease. Nat Rev Gastroenterol Hepatol. 13(2):88–110. doi:10.1038/nrgastro.2015.200.
  • Hoofnagle JH, Björnsson ES. 2019. Drug-induced liver injury - types and phenotypes. N Engl J Med. 381(3):264–273. doi:10.1056/NEJMra1816149.
  • Hou R, Goloubeva O, Neuberg DS, Strominger JL, Wilson SB. 2003. Interleukin-12 and interleukin-2-induced invariant natural killer T-cell cytokine secretion and perforin expression independent of T-cell receptor activation. Immunology. 110(1):30–37. doi:10.1046/j.1365-2567.2003.01701.x.
  • Hsu PS, Lai CL, Hu M, Santner-Nanan B, Dahlstrom JE, Lee CH, Ajmal A, Bullman A, Arbuckle S, Al Saedi A, et al. 2018. IL-2 enhances gut homing potential of human naive regulatory T cells early in life. J Immunol. 200(12):3970–3980. doi:10.4049/jimmunol.1701533.
  • Hudspeth K, Donadon M, Cimino M, Pontarini E, Tentorio P, Preti M, Hong M, Bertoletti A, Bicciato S, Invernizzi P, et al. 2016. Human liver-resident CD56(bright)/CD16(neg) NK cells are retained within hepatic sinusoids via the engagement of CCR5 and CXCR6 pathways. J Autoimmun. 66:40–50. doi:10.1016/j.jaut.2015.08.011.
  • Ishiyama K, Ohdan H, Ohira M, Mitsuta H, Arihiro K, Asahara T. 2006. Difference in cytotoxicity against hepatocellular carcinoma between liver and periphery natural killer cells in humans. Hepatology. 43(2):362–372. doi:10.1002/hep.21035.
  • Iyoda T, Ushida M, Kimura Y, Minamino K, Hayuka A, Yokohata S, Ehara H, Inaba K. 2010. Invariant NKT cell anergy is induced by a strong TCR-mediated signal plus co-stimulation. Int Immunol. 22(11):905–913. doi:10.1093/intimm/dxq444.
  • James AM, Hsu H-T, Dongre P, Uzel G, Mace EM, Banerjee PP, Orange JS. 2013. Rapid activation receptor- or IL-2-induced lytic granule convergence in human natural killer cells requires Src, but not downstream signaling. Blood. 121(14):2627–2637. doi:10.1182/blood-2012-06-437012.
  • Janas ML, Groves P, Kienzle N, Kelso A. 2005. IL-2 regulates perforin and granzyme gene expression in CD8+ T cells independently of its effects on survival and proliferation. J Immunol. 175(12):8003–8010. doi:10.4049/jimmunol.175.12.8003.
  • Jiang Y, Qin S, Wei X, Liu X, Guan J, Zhu H, Chang G, Chen Y, Lu H, Qian J, et al. 2021. Highly activated TRAIL + CD56bright NK cells are associated with the liver damage in HBV-LC patients. Immunol Lett. 232:9–19. doi:10.1016/j.imlet.2020.12.008.
  • John B, Crispe IN. 2004. Passive and active mechanisms trap activated CD8+ T cells in the liver. J Immunol. 172(9):5222–5229. doi:10.4049/jimmunol.172.9.5222.
  • Jukes J-P, Wood KJ, Jones ND. 2012. Bystander activation of iNKT cells occurs during conventional T-cell alloresponses. Am J Transplant. 12(3):590–599. doi:10.1111/j.1600-6143.2011.03847.x.
  • Kano A, Watanabe Y, Takeda N, Aizawa S, Akaike T. 1997. Analysis of IFN-gamma-induced cell cycle arrest and cell death in hepatocytes. J Biochem. 121(4):677–683. doi:10.1093/oxfordjournals.jbchem.a021639.
  • Kasahara T, Hooks JJ, Dougherty SF, Oppenheim JJ. 1983. Interleukin 2-mediated immune interferon (IFN-gamma) production by human T cells and T cell subsets. J Immunol. 130(4):1784–1789. doi:10.4049/jimmunol.130.4.1784.
  • Kashuba ADM, Hawke RL, Tonkin J, LeCluyse EL. 2000. Direct exposure to interleukins (IL)-2, -10 and -12 does not significantly suppress CYP3A activity in human hepatocytes. American Society for Clinical Pharmacology and Therapeutics Annual Meeting, Los Angeles, CA; 67:100.
  • Katz SC, Pillarisetty VG, Bleier JI, Shah AB, DeMatteo RP. 2004. Liver sinusoidal endothelial cells are insufficient to activate T cells. J Immunol. 173(1):230–235. doi:10.4049/jimmunol.173.1.230.
  • Kennedy NJ, Russell JQ, Michail N, Budd RC. 2001. Liver damage by infiltrating CD8+ T cells is Fas dependent. J Immunol. 167(11):6654–6662. doi:10.4049/jimmunol.167.11.6654.
  • Kikuchi-Maki A, Yusa S, Catina TL, Campbell KS. 2003. KIR2DL4 is an IL-2-regulated NK cell receptor that exhibits limited expression in humans but triggers strong IFN-gamma production. J Immunol. 171(7):3415–3425. doi:10.4049/jimmunol.171.7.3415.
  • Kleiner DE. 2014. Liver histology in the diagnosis and prognosis of drug-induced liver injury. Clin Liver Dis. 4(1):12–16. doi:10.1002/cld.371.
  • Klempner MS, Noring R, Mier JW, Atkins MB. 1990. An acquired chemotactic defect in neutrophils from patients receiving interleukin-2 immunotherapy. N Engl J Med. 322(14):959–965. doi: 10.1056/NEJM199004053221404.
  • Klugewitz K, Blumenthal-Barby F, Eulenburg K, Emoto M, Hamann A. 2004. The spectrum of lymphoid subsets preferentially recruited into the liver reflects that of resident populations. Immunol Lett. 93(2-3):159–162. doi:10.1016/j.imlet.2004.03.007.
  • Klugewitz K, Topp SA, Dahmen U, Kaiser T, Sommer S, Kury E, Hamann A. 2002. Differentiation-dependent and subset-specific recruitment of T-helper cells into murine liver. Hepatology. 35(3):568–578. doi:10.1053/jhep.2002.31310.
  • Knapen D, Vergauwen L, Villeneuve DL, Ankley GT. 2015. The potential of AOP networks for reproductive and developmental toxicity assay development. Reprod Toxicol. 56:52–55. doi:10.1016/j.reprotox.2015.04.003.
  • Knolle PA, Schmitt E, Jin S, Germann T, Duchmann R, Hegenbarth S, Gerken G, Lohse A. 1999. Induction of cytokine production in naive CD4+ T cells by antigen-presenting murine liver sinusoidal endothelial cells but failure to induce differentiation toward Th1 cells. Gastroenterology. 116(6):1428–1440. doi:10.1016/S0016-5085(99)70508-1.
  • Kogure T, Fujinaga H, Niizawa A, Hai LX, Shimada Y, Ochiai H, Terasawa K. 1999. Killer-cell inhibitory receptors, CD158a/b, are upregulated by interleukin-2, but not interferon-gamma or interleukin-4. Mediators Inflamm. 8(6):313–318. doi:10.1080/09629359990324.
  • Kolios G, Valatas V, Kouroumalis E. 2006. Role of Kupffer cells in the pathogenesis of liver disease. World J Gastroenterol. 12(46):7413–7420. doi:10.3748/wjg.v12.i46.7413.
  • Konjević G, Mirjačić Martinović K, Vuletić A, Radenković S. 2010. Novel aspects of in vitro IL-2 or IFN-α enhanced NK cytotoxicity of healthy individuals based on NKG2D and CD161 NK cell receptor induction. Biomed Pharmacother. 64(10):663–671. doi:10.1016/j.biopha.2010.06.013.
  • Kubes P, Jenne C. 2018. Immune responses in the liver. Annu Rev Immunol. 36(1):247–277. doi:10.1146/annurev-immunol-051116-052415.
  • Labuda T, Wendt J, Hedlund G, Dohlsten M. 1998. ICAM-1 costimulation induces IL-2 but inhibits IL-10 production in superantigen-activated human CD4+ T cells. Immunology. 94(4):496–502. doi:10.1046/j.1365-2567.1998.00540.x.
  • Lalor PF, Edwards S, McNab G, Salmi M, Jalkanen S, Adams DH. 2002. Vascular adhesion protein-1 mediates adhesion and transmigration of lymphocytes on human hepatic endothelial cells. J Immunol. 169(2):983–992. doi:10.4049/jimmunol.169.2.983.
  • Lalor PF, Sun PJ, Weston CJ, Martin‐Santos A, Wakelam MJO, Adams DH. 2007. Activation of vascular adhesion protein‐1 on liver endothelium results in an NF‐κB–dependent increase in lymphocyte adhesion. Hepatology. 45(2):465–474. doi:10.1002/hep.21497.
  • Lentsch AB, Miller FN, Edwards MJ. 1997. Interleukin-2-induced hepatic injury involves temporal patterns of cell adhesion in the microcirculation. Am J Physiol. 272(4 Pt 1):G727–31. doi:10.1152/ajpgi.1997.272.4.G727.
  • Levental I, Levental KR, Heberle FA. 2020. Lipid rafts: controversies resolved, mysteries remain. Trends Cell Biol. 30(5):341–353. doi:10.1016/j.tcb.2020.01.009.
  • Li J, Gyorffy S, Lee S, Kwok CS. 1996. Effect of recombinant human interleukin 2 on neutrophil adherence to endothelial cells in vitro. Inflammation. 20(4):361–372. doi:10.1007/BF01486739.
  • Li X, Tang J, Mao Y. 2022. Incidence and risk factors of drug-induced liver injury. Liver Int. 42(9):1999–2014. doi:10.1111/liv.15262.
  • Li Y, Strick-Marchand H, Lim AI, Ren J, Masse-Ranson G, Dan L, Jouvion G, Rogge L, Lucas S, Bin L, Di Santo JP. Regulatory T cells control toxicity in a humanized model of IL-2 therapy. Nat Commun. 2017;8(1):1762. doi:10.1038/s41467-017-01570-9.
  • Liao W, Lin J-X, Leonard WJ. 2011a. IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation. Curr Opin Immunol. 23(5):598–604. doi:10.1016/j.coi.2011.08.003.
  • Liao W, Lin J-X, Wang L, Li P, Leonard WJ. 2011b. Cytokine receptor modulation by interleukin-2 broadly regulates T helper cell lineage differentiation. Nat Immunol. 12(6):551–559. doi:10.1038/ni.2030.
  • Liao W, Schones DE, Oh J, Cui Y, Cui K, Tae-Young R, Zhao K, Leonard WJ. 2008. Priming for T helper type 2 differentiation by interleukin 2-mediated induction of IL-4 receptor α chain expression. Nat Immunol. 9(11):1288–1296. doi:10.1038/ni.1656.
  • Lim CK, Abolhassani H, Appelberg SK, Sundin M, Hammarström L. 2019. IL2RG hypomorphic mutation: identification of a novel pathogenic mutation in exon 8 and a review of the literature. Allergy Asthma Clin Immunol. 15(1):2. doi:10.1186/s13223-018-0317-y.
  • Loetscher P, Seitz M, Baggiolini M, Moser B. 1996. Interleukin-2 regulates CC chemokine receptor expression and chemotactic responsiveness in T lymphocytes. J Exp Med. 184(2):569–577. doi:10.1084/jem.184.2.569.
  • López S, García-Serrano S, Gutierrez-Repiso C, Rodríguez-Pacheco F, Ho-Plagaro A, Santiago-Fernandez C, Alba G, Cejudo-Guillen M, Rodríguez-Cañete A, Valdes S, et al. 2018. Tissue-Specific Phenotype and Activation of iNKT Cells in Morbidly Obese Subjects: interaction with Adipocytes and Effect of Bariatric Surgery. Obes Surg. 28(9):2774–2782. doi:10.1007/s11695-018-3215-y.
  • Lu R-J, Zhang Y, Tang F-L, Zheng Z-W, Fan Z-D, Zhu S-M, Qian X-F, Liu N-N. 2016. Clinical characteristics of drug-induced liver injury and related risk factors. Exp Ther Med. 12(4):2606–2616. doi:10.3892/etm.2016.3627.
  • Mäenpää A, Jääskeläinen J, Carpén O, Patarroyo M, Timonen T. 1993. Expression of integrins and other adhesion molecules on NK cells; impact of IL-2 on short- and long-term cultures. Int J Cancer. 53(5):850–855. doi:10.1002/ijc.2910530524.
  • Mahmoudpour SH, Jankowski M, Valerio L, Becker C, Espinola-Klein C, Konstantinides S, Quitzau K, Barco S. 2019. Safety of low-dose subcutaneous recombinant interleukin-2: systematic review and meta-analysis of randomized controlled trials. Sci Rep. 9(1):7145. doi:10.1038/s41598-019-43530-x.
  • Malek TR. 2008. The biology of interleukin-2. Annu Rev Immunol. 26(1):453–479. doi:10.1146/annurev.immunol.26.021607.090357.
  • Marmor MD, Julius M. 2001. Role for lipid rafts in regulating interleukin-2 receptor signaling. Blood. 98(5):1489–1497. doi:10.1182/blood.V98.5.1489.
  • Martrus G, Kautz T, Lunemann S, Richert L, Glau L, Salzberger W, Goebels H, Langeneckert A, Hess L, Poch T, et al. 2017. Proliferative capacity exhibited by human liver-resident CD49a + CD25+ NK cells. PLoS One. 12(8):e0182532. doi:10.1371/journal.pone.0182532.
  • Masson MJ, Carpenter LD, Graf ML, Pohl LR. 2008. Pathogenic role of natural killer T and natural killer cells in acetaminophen-induced liver injury in mice is dependent on the presence of dimethyl sulfoxide. Hepatology. 48(3):889–897. doi:10.1002/hep.22400.
  • McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, Kirkwood JM, Gordon MS, Sosman JA, Ernstoff MS, et al. 2005. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 23(1):133–141. doi:10.1200/JCO.2005.03.206.
  • Mehal WZ, Azzaroli F, Crispe IN. 2001. Antigen presentation by liver cells controls intrahepatic T cell trapping, whereas bone marrow-derived cells preferentially promote intrahepatic T cell apoptosis. J Immunol. 167(2):667–673. doi:10.4049/jimmunol.167.2.667.
  • Mehal WZ, Juedes AE, Crispe IN. 1999. Selective retention of activated CD8+ T cells by the normal liver. J Immunol. 163(6):3202–3210. doi:10.4049/jimmunol.163.6.3202.
  • Meunier L, Larrey D. 2019. Drug-induced liver injury: biomarkers, requirements, candidates, and validation. Front Pharmacol. 10:1482. doi:10.3389/fphar.2019.01482.
  • Mier JW, Dinarello CA, Atkins MB, Punsal PI, Perlmutter DH. 1987. Regulation of hepatic acute phase protein synthesis by products of interleukin 2 (IL 2)-stimulated human peripheral blood mononuclear cells. J Immunol. 139(4):1268–1272.
  • Moon B-I, Kim TH, Seoh J-Y. 2015. Functional modulation of regulatory T cells by IL-2. PLoS One. 10(11):e0141864. doi:10.1371/journal.pone.0141864.
  • Nakagawa K, Miller FN, Sims DE, Lentsch AB, Miyazaki M, Edwards MJ. 1996. Mechanisms of interleukin-2-induced hepatic toxicity. Cancer Res. 56(3):507–510.
  • Nguyen TV, Ukairo O, Khetani SR, McVay M, Kanchagar C, Seghezzi W, Ayanoglu G, Irrechukwu O, Evers R. 2015. Establishment of a hepatocyte-Kupffer cell coculture model for assessment of proinflammatory cytokine effects on metabolizing enzymes and drug transporters. Drug Metab Dispos. 43(5):774–785. doi:10.1124/dmd.114.061317.
  • Norris S, Collins C, Doherty DG, Smith F, McEntee G, Traynor O, Nolan N, Hegarty J, O'Farrelly C. 1998. Resident human hepatitis lymphocytes are phenotypically different from circulating lymphocytes. J Hepatol. 28(1):84–90. doi:10.1016/S0168-8278(98)80206-7.
  • Numerof RP, Kotik AN, Dinarello CA, Mier JW. 1990. Pro-interleukin-1β production by a subpopulation of human T cells, but not NK cells, in response to interleukin-2. Cell Immunol. 130(1):118–128. doi:10.1016/0008-8749(90)90166-O.
  • OECD Series on Adverse Outcome Pathways. 2018. doi:10.1787/5jlv1m9d1g32-en.
  • Oestreich KJ, Mohn SE, Weinmann AS. 2012. Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile. Nat Immunol. 13(4):405–411. doi:10.1038/ni.2242.
  • Ohta A, Sekimoto M, Sato M, Koda T, Nishimura S, Iwakura Y, Sekikawa K, Nishimura T. 2000. Indispensable role for TNF-alpha and IFN-gamma at the effector phase of liver injury mediated by Th1 cells specific to hepatitis B virus surface antigen. J Immunol. 165(2):956–961. doi:10.4049/jimmunol.165.2.956.
  • Osada T, Morse MA, Lyerly HK, Clay TM. 2005. Ex vivo expanded human CD4+ regulatory NKT cells suppress expansion of tumor antigen-specific CTLs. Int Immunol. 17(9):1143–1155. doi:10.1093/intimm/dxh292.
  • Overwijk WW, Tagliaferri MA, Zalevsky J. 2021. Engineering IL-2 to give new life to T cell immunotherapy. Annu Rev Med. 72(1):281–311. doi:10.1146/annurev-med-073118-011031.
  • Patten DA, Wilson GK, Bailey D, Shaw RK, Jalkanen S, Salmi M, Rot A, Weston CJ, Adams DH, Shetty S. 2016. Human liver sinusoidal endothelial cells promote intracellular crawling of lymphocytes during recruitment: a new step in migration. Hepatology. 65(1):294–309. doi:10.1002/hep.28879.
  • Pedersen AE, Lauritsen JP. 2009. CD25 shedding by human natural occurring CD4 + CD25+ regulatory T cells does not inhibit the action of IL-2. Scand J Immunol. 70(1):40–43. doi:10.1111/j.1365-3083.2009.02268.x.
  • Perna A, Yang X, Li L. 2009. Effects of IL-2 and IL-15 on CXCR6 expression and cytokine production by human lymphocytes. J Immunol. 182(1_Supplement):98.26. doi:10.4049/jimmunol.182.Supp.98.26.
  • Polentarutti N, Allavena P, Bianchi G, Giardina G, Basile A, Sozzani S, Mantovani A, Introna M. 1997. IL-2-regulated expression of the monocyte chemotactic protein-1 receptor (CCR2) in human NK cells: characterization of a predominant 3.4-kilobase transcript containing CCR2B and CCR2A sequences. J Immunol. 158(6):2689–2694.
  • Proleukin® Product Monograph. 2018. Product monograph: proleukin (Aldesleukin). Submission Control No: 217665.
  • Ramme AP, Koenig L, Hasenberg T, Schwenk C, Magauer C, Faust D, Lorenz AK, Krebs A-C, Drewell C, Schirrmann K, et al. 2019. Autologous induced pluripotent stem cell-derived four-organ-chip. Future Sci OA. 5(8):FSO413. doi:10.2144/fsoa-2019-0065.
  • Robinson MW, Harmon C, O'Farrelly C. 2016. Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol. 13(3):267–276. doi:10.1038/cmi.2016.3.
  • Roifman CM. 2000. Human IL-2 receptor alpha chain deficiency. Pediatr Res. 48(1):6–11. doi:10.1203/00006450-200007000-00004.
  • Rollings CM, Sinclair LV, Brady HJM, Cantrell DA, Ross SH. 2018. Interleukin-2 shapes the cytotoxic T cell proteome and immune environment-sensing programs. Sci Signal. 11(526):eaap8112. doi:10.1126/scisignal.aap8112.
  • Römer PS, Berr S, Avota E, Na S-Y, Battaglia M, Berge I t, Einsele H, Hünig T. 2011. Preculture of PBMCs at high cell density increases sensitivity of T-cell responses, revealing cytokine release by CD28 superagonist TGN1412. Blood. 118(26):6772–6782. doi:10.1182/blood-2010-12-319780.
  • Ross SH, Cantrell DA. 2018. Signaling and Function of Interleukin-2 in T Lymphocytes. Annu Rev Immunol. 36(1):411–433. doi:10.1146/annurev-immunol-042617-053352.
  • Rudnicka K, Matusiak A, Chmiela M. 2015. CD25 (IL-2R) expression correlates with the target cell induced cytotoxic activity and cytokine secretion in human natural killer cells. Acta Biochim Pol. 62(4):885–894. doi:10.18388/abp.2015_1152.
  • Salmi M, Kalimo K, Jalkanen S. 1993. Induction and function of vascular adhesion protein-1 at sites of inflammation. J Exp Med. 178(6):2255–2260. doi:10.1084/jem.178.6.2255.
  • Scheibenbogen C, Keilholz U, Richter M, Andreesen R, Hunstein W. 1992. The interleukin-2 receptor in human monocytes and macrophages: regulation of expression and release of the α and β chains (p55 and p75). Res Immunol. 143(1):33–37. doi:10.1016/0923-2494(92)80077-X.
  • Schildberg FA, Wojtalla a, Siegmund SV, Endl E, Diehl L, Abdullah Z, Kurts C, Knolle PA. 2011. Murine hepatic stellate cells veto CD8 T cell activation by a CD54‐dependent mechanism. Hepatology. 54(1):262–272. doi:10.1002/hep.24352.
  • Schmidt-Arras D, Rose-John S. 2016. IL-6 pathway in the liver: from physiopathology to therapy. J Hepatol. 64(6):1403–1415. doi:10.1016/j.jhep.2016.02.004.
  • Schurich A, Berg M, Stabenow D, Böttcher J, Kern M, Schild H-J, Kurts C, Schuette V, Burgdorf S, Diehl L, et al. 2010. Dynamic regulation of CD8 T cell tolerance induction by liver sinusoidal endothelial cells. J Immunol. 184(8):4107–4114. doi:10.4049/jimmunol.0902580.
  • Schwartz RN, Stover L, Dutcher JP. 2002. Managing toxicities of high-dose interleukin-2. Oncology. 11(Suppl 13):11–20.
  • Seidler S, Zimmermann HW, Weiskirchen R, Trautwein C, Tacke F. 2012. Elevated circulating soluble interleukin-2 receptor in patients with chronic liver diseases is associated with non-classical monocytes. BMC Gastroenterol. 12(1):38. doi:10.1186/1471-230X-12-38.
  • Setoguchi R, Hori S, Takahashi T, Sakaguchi S. 2005. Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med. 201(5):723–735. doi:10.1084/jem.20041982.
  • Sharma R, Das A. 2018. IL-2 mediates NK cell proliferation but not hyperactivity. Immunol Res. 66(1):151–157. doi:10.1007/s12026-017-8982-3.
  • Shen T, Liu Y, Shang J, Xie Q, Li J, Yan M, Xu J, Niu J, Liu J, Watkins PB, et al. 2019. Incidence and etiology of drug-induced liver injury in Mainland China. Gastroenterology. 156(8):2230–2241.e11. doi:10.1053/j.gastro.2019.02.002.
  • Shojaie L, Ali M, Iorga A, Dara L. 2021. Mechanisms of immune checkpoint inhibitor-mediated liver injury. Acta Pharm Sin B. 11(12):3727–3739. doi:10.1016/j.apsb.2021.10.003.
  • Simone G d, Andreata F, Bleriot C, Fumagalli V, Laura C, Garcia-Manteiga JM, Di Lucia P, Gilotto S, Ficht X, Ponti FFd, et al. 2021. Identification of a Kupffer cell subset capable of reverting the T cell dysfunction induced by hepatocellular priming. Immunity. 54(9):2089–2100.e8. doi:10.1016/j.immuni.2021.05.005.
  • Siwicki M, Gort-Freitas NA, Messemaker M, Bill R, Gungabeesoon J, Engblom C, Zilionis R, Garris C, Gerhard GM, Kohl A, et al. 2021. Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy. Sci Immunol. 6(61):eabi7083. doi:10.1126/sciimmunol.abi7083.
  • Spolski R, Li P, Leonard WJ. 2018. Biology and regulation of IL-2: from molecular mechanisms to human therapy. Nat Rev Immunol. 18(10):648–659. doi:10.1038/s41577-018-0046-y.
  • Stauber DJ, Debler EW, Horton PA, Smith KA, Wilson IA. 2006. Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc Natl Acad Sci U S A. 103(8):2788–2793. doi:10.1073/pnas.0511161103.
  • Suk KT, Kim DJ, Kim CH, Park SH, Yoon JH, Kim YS, Baik GH, Kim JB, Kweon YO, Kim BI, et al. 2012. A prospective nationwide study of drug-induced liver injury in Korea. Am J Gastroenterol. 107(9):1380–1387. doi:10.1038/ajg.2012.138.
  • Sunman JA, Hawke RL, LeCluyse EL, Kashuba ADM. 2004. Kupffer cell-mediated IL-2 suppression of CYP3A activity in human hepatocytes. Drug Metab Dispos. 32(3):359–363. doi:10.1124/dmd.32.3.359.
  • Takeda K, Hayakawa Y, van Kaer L, Matsuda H, Yagita H, Okumura K. 2000. Critical contribution of liver natural killer T cells to a murine model of hepatitis. Proc Natl Acad Sci U S A. 97(10):5498–5503. doi:10.1073/pnas.040566697.
  • Taylor AE, Carey AN, Kudira R, Lages CS, Shi T, Lam S, Karns R, Simmons J, Shanmukhappa K, Almanan M, et al. 2018. Interleukin 2 promotes hepatic regulatory T cell responses and protects from biliary fibrosis in murine sclerosing cholangitis. Hepatology. 68(5):1905–1921. doi:10.1002/hep.30061.
  • Tinel M, Robin M-A, Doostzadeh J, Maratrat M, Ballet F, Fardel N, Kahwaji JE, Beaune P, Daujat M, Labbe G, et al. 1995. The interleukin-2 receptor down-regulates the expression of cytochrome P450 in cultured rat hepatocytes. Gastroenterology. 109(5):1589–1599. doi:10.1016/0016-5085(95)90648-7.
  • Todd JA, Evangelou M, Cutler AJ, Pekalski ML, Walker NM, Stevens HE, Porter L, Smyth DJ, Rainbow DB, Ferreira RC, et al. 2016. Regulatory T cell responses in participants with type 1 diabetes after a single dose of interleukin-2: a non-randomised, open label, adaptive dose-finding trial. PLoS Med. 13(10):e1002139. doi:10.1371/journal.pmed.1002139.
  • Toomer KH, Lui JB, Altman NH, Ban Y, Chen X, Malek TR. 2019. Essential and non-overlapping IL-2Rα-dependent processes for thymic development and peripheral homeostasis of regulatory T cells. Nat Commun. 10(1):1037. doi:10.1038/s41467-019-08960-1.
  • Tsuchida T, Friedman SL. 2017. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 14(7):397–411. doi:10.1038/nrgastro.2017.38.
  • Tu Z, Bozorgzadeh A, Crispe IN, Orloff MS. 2007. The activation state of human intrahepatic lymphocytes. Clin Exp Immunol. 149(1):186–193. doi:10.1111/j.1365-2249.2007.03415.x.
  • Umehara H, Takashima A, Minami Y, Bloom ET. 1993. Signal transduction via phosphorylated adhesion molecule, LFA-1 beta (CD18), is increased by culture of natural killer cells with IL-2 in the generation of lymphokine-activated killer cells. Int Immunol. 5(1):19–27. doi:10.1093/intimm/5.1.19.
  • Valle MBd, Av Klinteberg V, Alem N, Olsson R, Björnsson E. 2006. Drug-induced liver injury in a Swedish University hospital out-patient hepatology clinic. Aliment Pharmacol Ther. 24(8):1187–1195. doi:10.1111/j.1365-2036.2006.03117.x.
  • Varshney P, Yadav V, Saini N. 2016. Lipid rafts in immune signalling: current progress and future perspective. Immunology. 149(1):13–24. doi:10.1111/imm.12617.
  • Vega M, Verma M, Beswick D, Bey S, Hossack J, Merriman N, Shah A, Navarro V. 2017. The incidence of drug- and herbal and dietary supplement-induced liver injury: preliminary findings from gastroenterologist-based surveillance in the population of the state of Delaware. Drug Saf. 40(9):783–787. doi:10.1007/s40264-017-0547-9.
  • Vickovic S, Eraslan G, Salmén F, Klughammer J, Stenbeck L, Schapiro D, Äijö T, Bonneau R, Bergenstråhle L, Navarro JF, et al. 2019. High-definition spatial transcriptomics for in situ tissue profiling. Nat Methods. 16(10):987–990. doi:10.1038/s41592-019-0548-y.
  • Vignali DAA, Collison LW, Workman CJ. 2008. How regulatory T cells work. Nat Rev Immunol. 8(7):523–532. doi:10.1038/nri2343.
  • Villeneuve DL, Landesmann B, Allavena P, Ashley N, Bal-Price A, Corsini E, Halappanavar S, Hussell T, Laskin D, Lawrence T, et al. 2018. Representing the process of inflammation as key events in adverse outcome pathways. Toxicol Sci. 163(2):346–352. doi:10.1093/toxsci/kfy047.
  • Vinken M. 2020. Liver adverse outcome pathways: what’s in for the hepatologist? J Gastrointestin Liver Dis. 29(4):659–664. doi:10.15403/jgld-2809.
  • Wakabayashi K, Lian Z-X, Moritoki Y, Lan RY, Tsuneyama K, Chuang Y-H, Yang G-X, Ridgway W, Ueno Y, Ansari AA, et al. 2006. IL-2 receptor alpha(-/-) mice and the development of primary biliary cirrhosis. Hepatology. 44(5):1240–1249. doi:10.1002/hep.21385.
  • Wang KS, Ritz J, Frank DA. 1999. IL-2 induces STAT4 activation in primary NK Cells and NK Cell lines, but not in T Cells. The Journal of Immunology. 162(1):299–304. doi:10.4049/jimmunol.162.1.299.
  • Wang Y, Zhang C. 2019. The roles of liver-resident lymphocytes in liver diseases. Front Immunol. 10:1582. doi:10.3389/fimmu.2019.01582.
  • Wei S, Blanchard DK, Liu JH, Leonard WJ, Djeu JY. 1993. Activation of tumor necrosis factor-alpha production from human neutrophils by IL-2 via IL-2-R beta. J Immunol. 150(5):1979–1987. doi:10.4049/jimmunol.150.5.1979.
  • Wigmore SJ, Fearon KC, Maingay JP, Lai PB, Ross JA. 1997. Interleukin-8 can mediate acute-phase protein production by isolated human hepatocytes. Am J Physiol. 273(4):E720–6. doi:10.1152/ajpendo.1997.273.4.E720.
  • Wigmore SJ, Fearon KCH, Maingay JP, Garden OJ, Ross JA. 2002. Effect of interleukin-2 on peripheral blood mononuclear cell cytokine production and the hepatic acute phase protein response. Clin Immunol. 104(2):174–182. doi:10.1006/clim.2002.5244.
  • Wilkinson AL, Qurashi M, Shetty S. 2020. The role of sinusoidal endothelial cells in the axis of inflammation and cancer within the liver. Front Physiol. 11:990. doi:10.3389/fphys.2020.00990.
  • Wolkers MC, Bensinger SJ, Green DR, Schoenberger SP, Janssen EM. 2011. Interleukin-2 rescues helpless effector CD8+ T cells by diminishing the susceptibility to TRAIL mediated death. Immunol Lett. 139(1–2):25–32. doi:10.1016/j.imlet.2011.04.011.
  • Wong J, Johnston B, Lee SS, Bullard DC, Smith CW, Beaudet AL, Kubes P. 1997. A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature. J Clin Invest. 99(11):2782–2790. doi:10.1172/JCI119468.
  • Wylezinski LS, Hawiger J. 2016. Interleukin 2 activates brain microvascular endothelial cells resulting in destabilization of adherens junctions*. J Biol Chem. 291(44):22913–22923. doi:10.1074/jbc.M116.729038.
  • Yong KSM, Her Z, Tan SY, Tan WWS, Liu M, Lai F, Heng SM, Fan Y, Chang KTE, Wang C-I, et al. 2020. Humanized mouse as a tool to predict immunotoxicity of human biologics. Front Immunol. 11:553362. doi:10.3389/fimmu.2020.553362.
  • Young HA, Ortaldo JR. 1987. One-signal requirement for interferon-gamma production by human large granular lymphocytes. J Immunol. 139(3):724–727. doi:10.4049/jimmunol.139.3.724.
  • Yuan X, Gajan A, Chu Q, Xiong H, Wu K, Wu GS. 2018. Developing TRAIL/TRAIL death receptor-based cancer therapies. Cancer Metastasis Rev. 37(4):733–748. doi:10.1007/s10555-018-9728-y.
  • Zen Y, Yeh MM. 2018. Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury. Mod Pathol. 31(6):965–973. doi:10.1038/s41379-018-0013-y.
  • Zhang X, Sun S, Hwang I, Tough DF, Sprent J. 1998. Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity. 8(5):591–599. doi:10.1016/S1074-7613(00)80564-6.
  • Zhang Z, Gothe F, Pennamen P, James JR, McDonald D, Mata CP, Modis Y, Alazami AM, Acres M, Haller W, et al. 2019. Human interleukin-2 receptor β mutations associated with defects in immunity and peripheral tolerance. J Exp Med. 216(6):1311–1327. doi:10.1084/jem.20182304.
  • Zhao J, Zhang S, Liu Y, He X, Qu M, Xu G, Wang H, Huang M, Pan J, Liu Z, et al. 2020a. Single-cell RNA sequencing reveals the heterogeneity of liver-resident immune cells in human. Cell Discov. 6(1):22. doi:10.1038/s41421-020-0157-z.
  • Zhao S, Jiang J, Jing Y, Liu W, Yang X, Hou X, Gao L, Wei L. 2020b. The concentration of tumor necrosis factor-α determines its protective or damaging effect on liver injury by regulating Yap activity. Cell Death Dis. 11(1):70. doi:10.1038/s41419-020-2264-z.
  • Zhou W, Zhang F, Aune TM. 2003. Either IL-2 or IL-12 is sufficient to direct Th1 differentiation by nonobese diabetic T cells. J Immunol. 170(2):735–740. doi:10.4049/jimmunol.170.2.735.
  • Zimmermann HW, Seidler S, Gassler N, Nattermann J, Luedde T, Trautwein C, Tacke F. 2011. Interleukin-8 is activated in patients with chronic liver diseases and associated with hepatic macrophage accumulation in human liver fibrosis. PLoS One. 6(6):e21381. doi:10.1371/journal.pone.0021381.
  • Zorn E, Nelson EA, Mohseni M, Porcheray F, Kim H, Litsa D, Bellucci R, Raderschall E, Canning C, Soiffer RJ, et al. 2006. IL-2 regulates FOXP3 expression in human CD4+ CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood. 108(5):1571–1579. doi:10.1182/blood-2006-02-004747.

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