IL-1 inhibitors: novel agents in the treatment of rheumatoid arthritis

Bibliography

• PETTIPHER ER, HIGGS GA, HENDERSON B: Interleukin 1 induces leukocyte infiltration and cartilage proteo-glycan degradation in the synovial joint. Proc. Natl. Acad. Sci. USA (1986) 83:8749–8753.
   PubMed Web of Science ®Google Scholar
• •This study clearly demonstrated the role of IL-1 in induction of the early inflammatory events and subsequent cartilage damage in arthritic joints.
   Google Scholar
• STIMPSON SA, DALLDORF FG, OTTERNESS IG, SCHWABJH: Exacerbation of arthritis by IL-1 in rat joints previously injured by peptidoglycan-polysaccharide. Immunol (1988) 140:2964–2969.
   Web of Science ®Google Scholar
• HOM JT, BENDELE AM, CARLSON DG: In vivo admini-stration with IL-1 accelerates the development of collagen-induced arthritis in mice. J. Immunol (1988) 141:834–830.
   PubMed Web of Science ®Google Scholar
• HANNUM CH, WILCOX CJ, AREND WP et al.:Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature (1990) 343:336–340.
   PubMed Web of Science ®Google Scholar
• •Characterisation of sIL-1Ra.
   Google Scholar
• JENKINS JK, DRONG RF, SHUCK ME, BIENKOWSKI MJ, SLIGHTOM JL, AREND WP, SMITH JR MF: Intracellular interleukin-1 receptor antagonist promoter: cell type-specific and inducible regulatory regions. J. Immunol. (1997) 158:748–755.
   PubMed Web of Science ®Google Scholar
• •This reference demonstrates that production of sIL-1Ra and icIL-1Ral is controlled by two different promoter regions.
   Google Scholar
• BUTCHER C, STEINKASSERER A, TEJURA S, LENNARD AC: Comparison of two promoters controlling expression of secreted or intracellular IL-1 receptor antagonist. J. Immunol. (1996) 153:701–711.
   Web of Science ®Google Scholar
• •See reference [6] for annotation.
   Google Scholar
• HASKILL S, MARTIN G, VAN LE L et al: cDNA cloning of an intracellular form of the human interleukin 1 receptor antagonist associated with epithelium. Proc. Nati Acad. Sci. USA (1991) 88:3681–3680.
   PubMed Web of Science ®Google Scholar
• ••Cloning and characterisation of an intracellular isoform ofIL-1Ra (icIL-1Ral).
   Google Scholar
• MUZIO M, POLENTARUTTI N, SIRONI M et al.: Cloning and characterization of a new isoform of the interleukin 1 receptor antagonist. J. Exp. Med. (1995) 182:623–628.
   PubMed Web of Science ®Google Scholar
• •Cloning of another intracellular IL-1Ra mRNA produced by the insertion of an additional exon coding for 21 amino acids in the N-terminal region.
   Google Scholar
• MALYAK M, GUTHRIDGE JM, HANCE KR, DOWER SK, FREED JH, AREND WP: Characterization of a low molecular weight isoform of interleukin-1 receptor antagonist. J. Immunol. (1998) 161:1997–2003.
   PubMed Web of Science ®Google Scholar
• •Molecular characterisation of a third intracellular isoform of IL-1Ra. This isoform is produced by alternative translation initiation, mainly from sIL-1Ra mRNA.
   Google Scholar
• MALYAK M, SMITH JR MF, ABEL AA, HANCE KR, AREND WP: The differential production of three forms of interleukin-1 receptor antagonist by human neutro-phils and monocytes. j Immunol. (1998) 161:2004–2010.
   PubMed Web of Science ®Google Scholar
• GABAY C, SMITH JR. MF, EIDLEN D, AREND WP: Interleukin-1 receptor antagonist is an acute-phase protein. J. Clin. Invest (1997) 99:2930–2940.
   PubMed Web of Science ®Google Scholar
• ••This study demonstrated that IL-1Ra is produced by HepG2cells and human hepatocytes in primary culture in response to IL-1 and IL-6 in a manner similar to an acute-phase protein. Production of IL-1Ra by the liver can account for the presence of elevated levels of this cytokine in the serum of patients with inflammatory diseases.
   Google Scholar
• GABAY C, PORTER B, GUENETTE D, BILIR B, AREND WP: IL-4 and IL-13 enhance the effect of interleukin-1 on IL-1 receptor antagonist production by human primary hepatocytes and HepG2 cells. Differential regulation for C-reactive protein. Blood (1999) 93:1299–1307.
   Google Scholar
• GABAY C, SMITH JR MF, AREND WP: The human intracellular interleukin-1 receptor antagonist promoter regulates gene expression in keratinocytes and gastrointestinal epithelial cells in vivo. Cytokine (1999) 11: 561–570
   PubMed Web of Science ®Google Scholar
• KRZESICKI RF, HATFIELD CA, BIENKOWSKI MJ et al:Regulation of expression of IL-1 receptor antagonist protein in human synovial and dermal fibroblasts. J. Immunol. (1993) 150:4008–4000.
   PubMed Web of Science ®Google Scholar
• MUZIO M, POLENTARUTTI N, FACCHETTI F et al: Charac-terization of Type II intracellular IL-1 receptor antago-nist (L1-1ra3): a depot IL-lra. Eur. J. Immunol (1999) 29:781–788.
   PubMedGoogle Scholar
• LEVINE SJ, WU T, SHELHAMER JH: Extracellular releaseof the Type I intracellular IL-1 receptor antagonist from human airway epithelial cells. Differential effects of I1-4, 11–13, IFNy, and corticosteroids. Immunol. (1997) 158:5949–5957.
   Google Scholar
• LEE RT, BRIGGS WH, CHENG GC, ROSSITER HB, LIBBY P,KUPPER T: Mechanical deformation promotes secretion of IL-la and IL-1 receptor antagonist. J. Immunol. (1997) 159:5084–5088.
   PubMed Web of Science ®Google Scholar
• YOON HJ, ZHU Z, GWALTNEY JR JM, ELIAS JA: Rhinovirus regulation of IL-1 receptor antagonist in vivo and in vitro: a potential mechanism of symptom resolution. J. Immunol. (1999) 162:7461–7469.
   PubMed Web of Science ®Google Scholar
• •The results of this study suggest that intracellular IL-1Ral can play a role in the resolution of an acute inflammatory condition. icIL-1Ral is released by epithelial cells and binds cell surface IL-1 receptors, thus preventing the interaction of IL-1 with its receptors.
   Google Scholar
• WATSON JM, LOFQUIST AK, RINEHART CA et al.: The intracellular IL-1 receptor antagonist alters IL-1-inducible gene expression without blocking exogenous signaling by IL-113. J. Immunol. (1995) 155:4467–4475.
   PubMed Web of Science ®Google Scholar
• •This study demonstrated for the first time that icIL-1Ral can exert its biological effects inside cells without interacting with cell surface IL-1 receptors. icIL-1Ral downregulated the IL-1-induced GRO and IL-8 production by decreasing the stability of their mRNAs.
   Google Scholar
• HIRSCH E, IRIKURA VM, PAUL SM, HIRSH D: Functions of interleukin 1 receptor antagonist in gene knockout and overproducing mice. Proc. Natl. Acad. Sci. USA (1996) 93:11008–11013.
   PubMed Web of Science ®Google Scholar
• ••Using IL-1Ra knockout and overexpressing transgenic mice,the authors demonstrated that IL-1Ra exerts important physiologic functions in host defence.
   Google Scholar
• FUKUMOTO T, MATSUKAWA A, OHKAWARA S, TAKAGI K, YOSHINAGA M: Administration of neutralizing antibody against rabbit IL-1 receptor antagonist exacerbates lipopolysaccharide-induced arthritis in rabbits. IntLamm. Res. (1996) 45:479–485.
   Google Scholar
• •First study showing that IL-1Ra acts as an endogenous anti-inflammatory mediator in arthritis.
   Google Scholar
• MA Y, THORNTON S, BOIVIN GP, HIRSH D, HIRSCH R, HIRSCH E: Altered susceptibility to collagen induced arthritis in transgenic mice with aberrant expression of IL-1 receptor antagonist. Arthritis Rheum. (1998) 41:1798–1805.
   PubMed Web of Science ®Google Scholar
• •IL-1Ra gene knockout mice had a more severe form of collagen-induced arthritis than their control littermates, whereas transgenic mice overexpressing murine IL-1Ra were protected.
   Google Scholar
• MILLER LC, LYNCH EA, ISA S, LOGAN JW, DINARELLO CA, STEERE AC: Balance of synovial fluid IL-113 and IL-1 receptor antagonist and recovery from Lyme arthritis. Lancet (1993) 341:146–148.
   PubMed Web of Science ®Google Scholar
• •The balance between IL-1 and its natural antagonist, IL-1Ra, is important in the course of Lyme arthritis. Patients with an elevated IL-1Ra/IL-113 ratio in the synovial fluid exhibited a rapid resolution of acute attacks of arthritis, whereas patients with the reverse pattern had a more protracted course.
   Google Scholar
• AREND WP, MALYAK M, SMITH JR MF et al.: Binding ofIL-la, 11–113, and IL-1 receptor antagonist by soluble IL-1 receptors and levels of soluble IL-1 receptors in synovial fluids. j Immunol. (1994) 153:4766–4774.
   Google Scholar
• MALYAK M, SWANEY RE, AREND WP: Levels of synovialfluid interleukin-1 receptor antagonist in rheumatoid arthritis and other arthropathies. Potential contribu-tion from synovial fluid neutrophils. Arthritis Rheum. (1993) 36:781–789.
   PubMedGoogle Scholar
• MALYAK M, SMITH MFJR, ABEL AA, AREND WP: Periph-eral blood neutrophil production of interleukin-1 receptor antagonist and interleukin-10. J. Clin. Immunol. (1994) 14:20–30.
   PubMed Web of Science ®Google Scholar
• FIRESTEIN GS, BOYLE DL, YU C, PAINE MM, WHISENAND TD, ZVAIFLER NJ, AREND WP: Synovial interleukin-1 receptor antagonist and interleukin-1 balance in rheumatoid arthritis. Arthritis Rheum. (1994) 37:644–640.
   PubMed Web of Science ®Google Scholar
• ••This study examined the production of IL-1Ra isoforms bycells isolated from rheumatoid synovial tissues. sIL-1Ra was primarily produced by synovial macrophages, whereas synovial fibroblasts were the main source of icIL-1Ral. However, production of IL-1Ra was relatively low in comparison with IL-1 in RA.
   Google Scholar
• DELEURAN BW, CHU CQ, FIELD M, BRENNAN FM, KATSIKIS P, FELDMANN M, MAINI RN: Localization of interleukin-1 alpha, Type 1 interleukin-1 receptor and interleukin-1 receptor antagonist in the synovial membrane and cartilage/pannus junction in rheuma-toid arthritis. Br. J. Rheumatol. (1992) 31:801–809.
   PubMedGoogle Scholar
• •By immunohistochemistry, up to 90% of the cells in the cartilage pannus junction stained for IL-1, whereas only 10% expressed IL-1Ra protein, thus indicating a relatively low production of IL-1Ra as compared with IL-1 in the rheuma-toid synovium.
   Google Scholar
• FIRESTEIN GS, BERGER AE, TRACEY DE et al.: IL-1receptor antagonist protein production and gene expression in rheumatoid arthritis and osteoarthritis synovium. j Immunol. (1992) 149:1054–1062.
   PubMed Web of Science ®Google Scholar
• AREND WP, MALYAK M, GUTHRIDGE CJ, GABAY C: Interleukin-1 receptor antagonist: role in biology. Ann. Rev. Immunol. (1998) 16:27–55.
   PubMed Web of Science ®Google Scholar
• ••A thorough review on IL-1Ra.
   Google Scholar
• AREND WP, WELGUS HG, THOMPSON RC, EISENBERG SP:Biological properties of recombinant monocyte-derived interleukin 1 receptor antagonist. J. Clin. Invest. (1990) 85:1694–1690.
   PubMed Web of Science ®Google Scholar
• SECKINGER P, KAUFMANN M-T, DAYER J-M: An interleukin-1 inhibitor affects both cell-associated interleukin-1-induced T cell proliferation and PGE2/collagenase production by human dermal fibroblasts and synovial cells. Immunobiology (1990) 180:316–327.
   PubMed Web of Science ®Google Scholar
• SECKINGER P, KLEIN-NULEND J, ALANDER C,THOMPSON RC, DAYER J-M, RAISZ LG: Natural and recombinant human IL-1 receptor antagonists block the effects of IL-1 on bone resorption and prosta-glandin production. J. Immunol. (1990) 145:4181–4184.
   PubMed Web of Science ®Google Scholar
• SECKINGER P, YARON I, MEYER FA, YARON M, DAYER J-M: Modulation of the effects of interleukin-1 on glycosaminoglycan synthesis by the urine-derived interleukin-1 inhibitor, but not by interleukin-6. Arthritis Rheum. (1990) 33:1807–1814.
   PubMed Web of Science ®Google Scholar
• ••This study showed that IL-1Ra can prevent the effects of IL-1on cartilage damage.
   Google Scholar
• SMITH RJ, CHIN JE, SAM LM, JUSTEN JM: Biologic effectsof an interleukin-1 receptor antagonist protein on interleukin-1-stimulated cartilage erosion and chondrocyte responsiveness. Arthritis Rheum. (1991) 34:78–83.
   PubMed Web of Science ®Google Scholar
• SCHWAB JH, ANDERLE SK, BROWN RR, DALLDORF FG,THOMPSON RC: Pro- and anti-inflammatory roles of interleukin-1 in recurrence of bacterial cell wall-induced arthritis in rats. Infect. Immun. (1991) 59:4436–4442.
   PubMed Web of Science ®Google Scholar
• MATSUKAWA A, OHKAWARA S, MAEDA T, TAKAGI K, YOSHINAGA M: Production of IL-1 and IL-1 receptor antagonist and the pathological significance in lipopolysaccharide-induced arthritis in rabbits. Clin. Exp. Immunol. (1993) 93:206–211.
   PubMed Web of Science ®Google Scholar
• WOOLEY PH, WHALEN JD, CHAPMAN DL et al.: The effect of an interleukin-1 receptor antagonist protein on Type II collagen-induced arthritis and antigen-induced arthritis in mice. Arthritis Rheum. (1993) 36:1305–1314.
   PubMed Web of Science ®Google Scholar
• •This study demonstrated that exogenous administration of recombinant human IL-1Ra can decrease the frequency and severity of collagen-induced arthritis.
   Google Scholar
• HENDERSON B, THOMPSON RC, HARDINGHAM T, LEWTHWAITE J: Inhibition of interleukin-1-induced synovitis and articular cartilage proteoglycan loss in the rabbit knee by recombinant interleukin-1 receptor antagonist. Cytokine (1991) 3:246–240.
   PubMed Web of Science ®Google Scholar
• ROESSLER BJ, ALLEN ED, WILSON JM, HARTMAN JW, DAVIDSON BL: Adenoviral-mediated gene tranfer to rabbit synovium in vivo. J. Clin. Invest (1993) 92:1085–1080.
   PubMed Web of Science ®Google Scholar
• ROESSLER BJ, HARTMAN JW, VALLANCE DK, LATTA JM,JANISH SL, DAVIDSON BL: Inhibition of interleukin-1-induced effects in synoviocytes transduced with the human IL-1 receptor antagonist cDNA using an adenoviral vector. Hum. Gene Ther. (1995) 6:307–316.
   PubMed Web of Science ®Google Scholar
• BANDARA G, MUELLER GM, GALEA-LAURI J et al.: Intraar-ticular expression of biologically active interleukin 1 receptor antagonist protein by ex vivo gene transfer. Proc. Nati Acad. Sci. USA (1993) 90:10764–10768.
   PubMed Web of Science ®Google Scholar
• ••This paper demonstrated that intra-articular production ofIL-1Ra by ex vivo gene transfer could inhibit the biological effects of IL–1.
   Google Scholar
• MAKAROV SS, OLSEN JC, JOHNSTON WN, ANDERLE SK,BROWN RR, BALDWIN AS, HASKILL JS, SCHWAB JH: Suppression of experimental arthritis by gene transfer of interleukin 1 receptor antagonist cDNA. Proc. Nati Acad. Sci. USA (1996) 93:402–406.
   PubMed Web of Science ®Google Scholar
• OTANI K, NITA I, MACAULAY W, GEORGESCU HI, ROBBINS PD, EVANS CH: Suppression of antigen-induced arthritis in rabbits by ex vivo gene therapy. J. Immunol. (1996) 156:3558–3362.
   PubMed Web of Science ®Google Scholar
• BAKKER AC, JOOSTEN LAB, ARNTZ OJ et al. Prevention of murine collagen-induced arthritis in the knee and ipsilateral paw by local expression of human interleukin-1 receptor antagonist protein in the knee. Arthritis Rheum. (1997) 40:893–900.
   PubMed Web of Science ®Google Scholar
• •Local production of IL-1Ra in the knees had anti-inflammatory effects in other joints, thus suggesting that local gene therapy can be used in the treatment of a polyar-ticular and systemic disease such as RA.
   Google Scholar
• MULLER-LADNER U, ROBERTS CR et al.: Human IL-1Ra gene transfer into human synovial fibroblasts is chondroprotective. j Immunol. (1997) 158:3492–3498.
   PubMed Web of Science ®Google Scholar
• ••This study demonstrated that IL-1Ra had a chondroprotec-tive effect in a in vivo model system where rheumatoid synovial fibroblasts were co-implanted with cartilage into SCID mice. Fibroblasts transduced with a retroviral vector containing sIL-1Ra cDNA inhibited the chondrocyte-mediated cartilage degradation. However, the invasion of fibroblasts into the cartilage was not altered by IL-1Ra.
   Google Scholar
• BARAGI VM, RENKIEWICZ RR, JORDAN H, BONADIO J, HARTMAN JW, ROESSLER BJ: Transplantation of transduced chondrocytes protects articular cartilage from interleukin-1-induced extracellular matrix degradation. J. Clin. Invest. (1995) 96:2454–2460.
   PubMed Web of Science ®Google Scholar
• ••Transplantation of chondrocytes transduced with IL-1Raattenuated the progression of cartilage damage in osteoarthritis.
   Google Scholar
• PELLETIER J-P, CARON JP, EVANS C et al: In vivo suppres- sion of early experimental osteoarthritis by interleukin-1 receptor antagonist using gene therapy. Arthritis Rheum. (1997) 40:1012–1019.
   PubMed Web of Science ®Google Scholar
• ••Local delivery of IL-1Ra by gene therapy had a chondropro-tective effect in an experimental model of osteoarthritis.
   Google Scholar
• GHIVIZZANI SC, KANG R, MUZZONIGRO T et al.: Therapy for arthritis - treatment of the first three patients. Arthritis Rheum. (1997) 40:S223. (Abstract).
   Google Scholar
• CAMPION GV, LEBSACK ME, LOOKABAUGH J, GORDON G, CATALANO MA: Dose-range and dose-frequency study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. Arthritis Rheum. (1996) 39:1092–1101.
   PubMed Web of Science ®Google Scholar
• •First clinical trial of recombinant human IL-1Ra in the treatment of RA patients.
   Google Scholar
• BRESNIHAN B, ALVARO-GRACIA JM, COBBY M et al.: Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum. (1998) 41:2196–2204.
   PubMed Web of Science ®Google Scholar
• ••Randomised, double-blind, placebo-controlled study. Theresults showed that patients who received IL-1Ra demonstrated a significant improvement in several clinical parameters in comparison with the placebo group. In addition, patients treated with the highest dose of IL-1Ra exhibited a reduced frequency and severity of radiological signs of joint erosions.
   Google Scholar
• NUKI G, ROZMAN B, PAVELKA K, EMERY P, LOOKABAUGH J, MUSIKIC P: Interleukin-1 receptor antagonist continues to demonstrate clinical improve-ment in rheumatoid arthritis. Arthritis Rheum. (1997) 40:S224. (Abstract).
   Google Scholar
• COLLINS D, MCABEE T, WOODWARD M, FRAZIER J, CHLIPALA E, BENDELE A: A slow release formulation of interleukin-1 receptor antagonist (IL-1Ra) exhibits improved in vivo activity. Arthritis Rheum. (1997) 40:S180. (Abstract).
   Google Scholar
• WILLIAMS RO, MAURI C, MASON LJ et al.: Therapeutic actions of cyclosporine and anti-tumor necrosis factor a in collagen-induced arthritis and the effect of combination therapy. Arthritis Rheum. (1998) 41:1806–1812.
   PubMed Web of Science ®Google Scholar
• •Combination of a biologic agent with a known antirheu-matic drug had additive anti-inflammatory effects in an experimental model of RA.
   Google Scholar
• MAINI RN, BREEDVELD FC, KALDEN JR et al.: Therapeutic efficacy of multiple intravenous infusions of tumor necrosis a monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. (1998) 41:1552–1563.
   PubMed Web of Science ®Google Scholar
• ••This study demonstrated that combination therapy of lowdose antiTNF-a monoclonal antibody with methotrexate was well-tolerated. In addition, the authors observed that coadministration of low dose antiTNF-a monoclonal antibody with methotrexate had a synergistic effect on the clinical response.
   Google Scholar
• BENDELE AM, SENNELLO G, MCABEE T, FRAZIER J, CHLIPALA E, RICH B: Effects of interleukin-1 receptor antagonist alone and in combination with methotrexate in adjuvant arthritic rats. J. Rheumatol. (1999) 26:1225–1229.
   PubMed Web of Science ®Google Scholar
• •Combination of IL-1Ra with methotrexate was effective in reducing both the inflammatory process and joint destruction.
   Google Scholar
• COHEN S, HURD E, CUSH JJ et al.: Treatment of interleukin-1 receptor antagonist in combination with methotrexate in rheumatoid arthritis patients. Arthritis Rheum. (1999) 42: S273.
   Google Scholar
• •First study on combination therapy of IL-1Ra with methotrexate in RA. 419 active RA patients despite being treated with methotrexate received either injections of placebo or IL-1Ra. The results showed that patients receiving IL-1Ra had a better clinical response than the placebo group.
   Google Scholar
• GHIVIZZANI SC, LECHMAN ER, KANG R et al.: Direct adenovirus-mediated gene transfer of interleukin 1 and tumor necrosis factor a soluble receptors to rabbit knees with experimental arthritis has local and distal anti-arthritic effects. Proc. Nati Acad. Sci. USA (1998) 95:4613–4618.
   PubMed Web of Science ®Google Scholar
• ••Combination of anti-TNF-a and anti-IL-1 was more effectivethan either treatment used alone.
   Google Scholar
• KULPER S, JOOSTEN LA, BENDELE AM et al.: Different roles of tumour necrosis factor a and interleukin 1 in murine streptococcal cell wall arthritis. Cytokine (1998) 10:690–702.
   PubMed Web of Science ®Google Scholar
• FEIGE U, HU Y-L, JULIAN E, DURYEA D: Combininganti-IL-1 and anti-TNF treatments provides better efficacy in rat adjuvant arthritis than does either agent alone. Arthritis Rheum. (1999) 42:S383.
   Google Scholar
• BENDELE AM, CHLIPALA ES, RICH WR, EDWARDS CK: Combination benefit of treatment with recombinant human interleukin-1 receptor antagonist (IL-1Ra) and pegylated recombinant human soluble tumor necrosis factor receptor Type I (PEG sTNE-R0 in animal models of rheumatoid arthritis. Arthritis Rheum. (1999) 42:S171.
   Google Scholar
• PALEOLOG EM, YOUNG S, STARK AC, MCCLOSKEY RV,FELDMANN M, MAINI RN: Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor alpha and interleukin-1 in rheumatoid arthritis. Arthritis Rheum. (1998) 41:1258–1265.
   PubMed Web of Science ®Google Scholar
• SEITZ M, LOETCHER P, DEWALD B, TOWBIN H, RORDORF C, GALLATI H, GERBER NJ: Interleukin 1 (IL-1) receptor antagonist, soluble tumor necrosis factor receptors, 11-113, and 11-8 markers of remission in rheumatoid arthritis during treatment with methotrexate. j Rheumatol (1996) 23:1512–1516.
   PubMed Web of Science ®Google Scholar
• SEITZ M, ZWICKER M, LOETSCHER P: Effects ofmethotrexate on differenciation of monocytes and production of cytokine inhibitors by monocytes. Arthritis Rheum. (1998) 41:2032–2038.
   PubMed Web of Science ®Google Scholar
• SHINGU M, FUJIKAWA Y, WADA T, NONAKA S, NOBUNAGA M: Increased IL-1 receptor antagonist (11-1ra) production and decreased 11-18/IL-1 ra ratio in mononuclear cells from rheumatoid arthritis patients. Br. J. Rheumatol. (1995) 34:24–30.
   PubMedGoogle Scholar
• DINARELLO CA: Biologic basis for interleukin-1 in disease. Blood (1996) 87:2095–2147.
   PubMed Web of Science ®Google Scholar
• ••A thorough review on IL-1.
   Google Scholar
• AREND WP: Interleukin-1 receptor antagonist. Adv. Immunol. (1993) 54:167–227.
   PubMed Web of Science ®Google Scholar
• DE WAAL MALEFYT R, FIGDOR CG et al.: Effects of 11-13on phenotype, cytokine production, and cytotoxic function of human monocytes. Comparison with 11–4 and modulation by IFNy or 11–10. J. Immunol. (1993) 151:6370–6381.
   Google Scholar
• ALLEN JB, WONG HL, COSTA GL, BIENKOWSKI MJ, WAHLSM: Suppression of monocyte function and differential regulation of 11-1 and IL-1Ra by 11-4 contribute to resolution of experimental arthritis. J. Immunol. (1993) 151:4344–4351.
   PubMed Web of Science ®Google Scholar
• •Shows the therapeutic effects of Th2 cytokines on experi-mental models of arthritis.
   Google Scholar
• BESSIS N, BOISSIER MC, FERRARA P, BLANKENSTEIN T, FRADELIZI D: Attenuation of collagen-induced arthritis in mice by treatment with vector cells engineered to secrete interleukin-13. Eur. J. Immunol. (1996) 26:2399–2403.
   PubMed Web of Science ®Google Scholar
• •See reference [70] for annotation.
   Google Scholar
• WALMSLEY M, KATSIKIS PD, ABNEY E, PARRY S, WILLIAMS RO, MAINI RN, FELDMANN M: Interleukin-10 inhibition of the progression of established collagen-induced arthritis. Arthritis Rheum. (1995) 39:495–503.
   Web of Science ®Google Scholar
• •See reference [70] for annotation.
   Google Scholar
• LI P, ALLEN H, BANERJEE S et al. Mice deficient in
   Google Scholar
• -10-converting enzyme are defective in production of mature 11-18 and resistant to endotoxic shock. Cell (1995) 80:401.
   PubMed Web of Science ®Google Scholar
• KU G, FAUST T, LAUFFER LL, LIVINGSTON DJ, HARDING MW: Interleukin-18 converting enzyme inhibition blocks progression of Type II collagen-induced arthritis in mice. Cytokine (1996) 8:377–386.
   Google Scholar
• FANTUZZI G, KU G, HARDING MW et al: Response to local inflammation of IL-16-converting enzyme- deficient mice. J. Immunol. (1997) 158:1818–1824.
   PubMed Web of Science ®Google Scholar
• •This study showed the processing of pro-IL-1I3 by other enzymatic pathways than IL-1I3-convertase enzyme.
   Google Scholar
• SCHONBECK U, MACH F, LIBBY P: Generation of biologically active LL-113 by matrix metalloproteinases: a novel caspase-l-independent pathway of IL-16 processing. J. Immunol (1998) 161:3340–3346.
   PubMed Web of Science ®Google Scholar
• •See reference [75] for annotation.
   Google Scholar
• DOWER SK, FANSLOW W, JACOBS C, WAUGH S, SIMS JE, WIDMER MB: Interleukin-1 antagonists. Therapeutic Immunol. (1994) 1:113–122.
   PubMedGoogle Scholar
• DREVLOW BE, LOVIS R, HAAG MA et al: Recombinant human interleukin-1 receptor Type I in the treatment of patients with active rheumatoid arthritis. Arthritis Rheum. (1996) 39:257–265.
   PubMed Web of Science ®Google Scholar
• COLOTTA F, DOWER SK, SIMS JE, MANTOVANI A: The Type II 'decoy' receptor: a novel regulatory pathway for interleukin 1. Immunol. Today (1994) 15:562–566.
   PubMedGoogle Scholar
• ••A review article on soluble IL-1 receptor Type II. Thisreceptor is cleaved by a metalloproteinase and is present in different body fluids. Soluble IL-1R Type II binds IL-1I3 with a high affinity and can prevent its binding to cell surface IL-1R Type I.
   Google Scholar
• BURGER D, CHICHEPORTICHE R, GIRI JG, DAYER J-M: The inhibitory activity of human interleukin-1 receptor antagonist is enhanced by Type II interleukin-1 soluble receptor and hindered by Type I interleukin-1 soluble receptor. J. Clin. Invest. (1995) 96:38–41.
   PubMed Web of Science ®Google Scholar
• ••This study demonstrated that soluble IL-1R Type II supple-mented the inhibitory effect of IL-1Ra.
   Google Scholar
• DAWSON J, ENGELHARDT P, KASTELIC T, CHENEVAL D, MACKENZIE A, RAMAGE P: Effects of soluble interleukin-1 Type II receptor on rabbit antigen-induced arthritis: clinical, biochemical and histological assessment. Rheumatology (1999) 38:401–406.
   PubMed Web of Science ®Google Scholar
• •Administration of soluble IL-1R Type II attenuated both the inflammatory response and joint damage in rabbit antigen-induced arthritis.
   Google Scholar
• BESSIS N, GUERY L, MANTOVANI A, VECCHI A, FRADELIZI D, BOISSIER M-C: The Type II receptor of interleukin-1 inhibits murine collagen-induced arthritis. Arthritis Rheum. (1999) 42:S118.
   Google Scholar
• AKESON AL, WOODS CW, HSIEH LC et al.: AF12198, anovel low molecular weight antagonist, selectively binds the human Type I interleukin (IL)-1 receptor and blocks in vivo responses to IL-1. J. Biol. Chem. (1996) 271:30517–30523.
   PubMed Web of Science ®Google Scholar
• SCHEINMAN RI, COGSWELL PC, LOFQUIST AK, BALDWIN AS: Role of transcriptional activation of hcBcc in mediation of immunosuppression by glucocorticoids. Science (1995) 270:283–286.
   PubMed Web of Science ®Google Scholar
• ••This study demonstrates that glucocorticoids inhibit theNF-x13 transcriptional activity by increasing production of its cytoplasmic inhibitor, Ia. The results presented in these papers provide a novel mechanism through which glucocorticoids can exert their immunosuppressive effects.
   Google Scholar
• AUPHAN N, DIDONATO JA, ROSETTE C, HELMBERG A, KARIN M: Immunosuppression by glucocorticoids: inhibition of NF-KB activity through induction of IKB synthesis. Science (1995) 270:286–290.
   PubMed Web of Science ®Google Scholar
• ••See reference [84] for annotation.
   Google Scholar
• BAEUERLE PA, BAICHWAL VR: NF-x13 as a frequent target for immunosuppressive and anti-inflammatory molecules. Adv. Immunol (1997) 65:111–137.
   PubMed Web of Science ®Google Scholar
• ••A thorough review on the role of NF-kB in the immuneresponse.
   Google Scholar
• HANDEL ML, MCMORROW LB, GRAVALLESE EM: Nuclearfactor-a in rheumatoid synovium. Localization of p50 and p65. Arthritis Rheum. (1995) 38:1762–1770.
   Google Scholar
• ROSHAK AK, JACKSON JR, MCGOUGH K, CHABOT-FLETCHER M, MOCHAN E, MARSHALL LA: Manipulation of distinct NF-KB proteins alters interleukin-1I3-induced human rheumatoid synovial fibroblast prostaglandin E2 formation. J. Biol. Chem. (1996) 271:31496–31501.
   PubMed Web of Science ®Google Scholar
• BONDESON J, FOXWELL B, BRENNAN F, FELDMANN M: Defining therapeutic targets by using adenovirus: blocking NF-KB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators. Proc. Natl. Acad. Sci. USA (1999) 96:5668–5673.
   PubMed Web of Science ®Google Scholar
• ••This study demonstrated that NF-kB is involved in produc-tion of pro-inflammatory cytokines and metalloproteinases, and thus represents an interesting therapeutic target in RA.
   Google Scholar
• CONNER EM, FUSELER JW, DAVIS JM et al.: Selective proteasome inhibition attenuates experimental polyarthritis via inhibition of nuclear transcription factor KB (NF-kB) activation. Arthritis Rheum. (1997) 40:S322.
   Google Scholar
• SEETHARAMAN R, MORA AL, NABOZNY G, BOOTHBY M, CHEN J: Essential role of T cell NF-KB activation in collagen-induced arthritis. J. Immunol. (1999) 163:1577–1583.
   PubMed Web of Science ®Google Scholar
• •This paper showed that NF-kB activation in T-lymphocytes is involved in the pathogenesis of collagen-induced arthritis.
   Google Scholar
• ANGEL P, KARIN M: The role of Jun, Fos and AP-1 complex in cell-proliferation and transformation. Biochim. Biophys. Acta (1991) 1072:129–157.
   PubMed Web of Science ®Google Scholar
• SHIOZAWA S, SHIOZAWA K, FUJITA T, TOKUHISA T: Destructive arthritis without lymphocyte infiltration in 112-c-fos transgenic mice. J. Immunol (1992) 148:3100–3104.
   PubMed Web of Science ®Google Scholar
• KUROKI Y, SHIOZAWA S, SUGIMOTO T et al: Constitutivec-fos expression in osteoblastic MC3T3-E1 cells stimulates osteoclast maturation and osteoclastic bone resorption. Clin. Exp. Immunol. (1994) 95:536–539.
   PubMed Web of Science ®Google Scholar
• SHIOZAWA S, SHIMIZU K, TANAKA K, HINO K: Studieson the contribution of c-fos/AP-1 to arthritic joint destruction. J. Clin. Invest. (1997) 99:1210–1216.
   PubMed Web of Science ®Google Scholar
• •The transcription factor AP-1 is involved in the pathogenesis of collagen-induced arthritis, and thus represent another potential intracellular target in the treatment of RA.
   Google Scholar
• WORONICZ JD, GAO X, CAO Z, ROTHE M, GOEDDEL DV: Ix13 kinase-I3: NF-03 activation and complex formation with La kinase-a and NIK. Science (1997) 278:866–870.
   PubMed Web of Science ®Google Scholar