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01-06-2006 | Original Article

Interleukin-12 to interleukin ‘infinity’: the rationale for future therapeutic cytokine targeting

Authors: E. J. R. Anderson, M. A. McGrath, T. Thalhamer, I. B. McInnes

Published in: Seminars in Immunopathology | Issue 4/2006

Excerpt

Chronic inflammatory disorders comprise a significant source of morbidity, mortality and societal cost. Conventional therapeutics have relied on rather broad spectrum inhibitors derived often from the cytotoxic drug armamentarium, or from non-specific immune modulatory agents derived on the basis of broad immune suppression. More recently has arisen the notion that immune-based therapies might be optimised on the basis of underlying disease pathogenesis. In this respect, the success of TNF blockade across a range of inflammatory diseases, initially rheumatoid arthritis, then psoriasis and Crohn’s disease, has provoked significant interest in understanding the wider biology and functional effects of a large number of pro-inflammatory cytokines in the context of human disease. The present review will consider those novel cytokines that may offer therapeutic utility in the future. Cytokines that are already subjects to clinical intervention, including TNF, IL-1 and IL-6, are not considered in this review; their relevant biology has been extensively reviewed elsewhere in this volume. Instead, we shall focus on those cytokines characteristically synthesised during the innate immune responses with activities of relevance not only in the chronic inflammatory lesion but also in the evolution of subsequent adaptive (autoimmune responses). …

Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S, Loudon R, Sherman F, Perussia B, Trinchieri G (1989) Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med 170:827–845PubMed

Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA (2000) Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13:715–725PubMed

Pflanz S, Timans JC, Cheung J, Rosales R, Kanzler H, Gilbert J, Hibbert L, Churakova T, Travis M, Vaisberg E, Blumenschein WM, Mattson JD, Wagner JL, To W, Zurawski S, McClanahan TK, Gorman DM, Bazan JF, de Waal Malefyt R, Rennick D, Kastelein RA (2002) IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells. Immunity 16:779–790PubMed

Presky DH, Yang H, Minetti LJ, Chua AO, Nabavi N, Wu CY, Gately MK, Gubler U (1996) A functional interleukin 12 receptor complex is composed of two beta-type cytokine receptor subunits. Proc Natl Acad Sci U S A 93:14002–14007PubMed

Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, Pflanz S, Zhang R, Singh KP, Vega F, To W, Wagner J, O’Farrell AM, McClanahan T, Zurawski S, Hannum C, Gorman D, Rennick DM, Kastelein RA, de Waal Malefyt R, Moore KW (2002) A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol 168:5699–5708PubMed

Pflanz S, Hibbert L, Mattson J, Rosales R, Vaisberg E, Bazan JF, Phillips JH, McClanahan TK, de Waal Malefyt R, Kastelein RA (2004) WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J Immunol 172:2225–2231PubMed

Trinchieri G, Pflanz S, Kastelein RA (2003) The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. Immunity 19:641–644PubMed

Trinchieri G (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3:133–146PubMed

Manetti R, Parronchi P, Giudizi MG, Piccinni MP, Maggi E, Trinchieri G, Romagnani S (1993) Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med 177:1199–1204PubMed

10.

Wittmann M, Kienlin P, Mommert S, Kapp A, Werfel T (2002) Suppression of IL-12 production by soluble CD40 ligand: evidence for involvement of the p44/42 mitogen-activated protein kinase pathway. J Immunol 168:3793–3800PubMed

11.

Mullen AC, High FA, Hutchins AS, Lee HW, Villarino AV, Livingston DM, Kung AL, Cereb N, Yao TP, Yang SY, Reiner SL (2001) Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science 292:1907–1910PubMed

12.

Bettelli E, Kuchroo VK (2005) IL-12- and IL-23-induced T helper cell subsets: birds of the same feather flock together. J Exp Med 201:169–171PubMed

13.

Hibbert L, Pflanz S, De Waal Malefyt R, Kastelein RA (2003) IL-27 and IFN-alpha signal via Stat1 and Stat3 and induce T-Bet and IL-12Rbeta2 in naive T cells. J Interferon Cytokine Res 23:513–522PubMed

14.

Lucas S, Ghilardi N, Li J, de Sauvage FJ (2003) IL-27 regulates IL-12 responsiveness of naive CD4+ T cells through Stat1-dependent and -independent mechanisms. Proc Natl Acad Sci U S A 100:15047–15052PubMed

15.

Hamano S, Himeno K, Miyazaki Y, Ishii K, Yamanaka A, Takeda A, Zhang M, Hisaeda H, Mak TW, Yoshimura A, Yoshida H (2003) WSX-1 is required for resistance to Trypanosoma cruzi infection by regulation of proinflammatory cytokine production. Immunity 19:657–667PubMed

16.

Villarino AV, Huang E, Hunter CA (2004) Understanding the pro- and anti-inflammatory properties of IL-27. J Immunol 173:715–720PubMed

17.

Monteleone G, Biancone L, Marasco R, Morrone G, Marasco O, Luzza F, Pallone F (1997) Interleukin 12 is expressed and actively released by Crohn’s disease intestinal lamina propria mononuclear cells. Gastroenterology 112:1169–1178PubMed

18.

Lauwerys BR, Van Snick J, Houssiau FA (2002) Serum IL-12 in systemic lupus erythematosus: absence of p70 heterodimers but presence of p40 monomers correlating with disease activity. Lupus 11:384–387PubMed

19.

Yawalkar N, Karlen S, Hunger R, Brand CU, Braathen LR (1998) Expression of interleukin-12 is increased in psoriatic skin. J Invest Dermatol 111:1053PubMed

20.

Leonard JP, Waldburger KE, Goldman SJ (1995) Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. J Exp Med 181:381–386PubMed

21.

Lee E, Trepicchio WL, Oestreicher JL, Pittman D, Wang F, Chamian F, Dhodapkar M, Krueger JG (2004) Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med 199:125–130PubMed

22.

Goldberg R, Zohar Y, Wildbaum G, Geron Y, Maor G, Karin N (2004) Suppression of ongoing experimental autoimmune encephalomyelitis by neutralizing the function of the p28 subunit of IL-27. J Immunol 173:6465–6471PubMed

23.

Li J, Gran B, Zhang GX, Rostami A, Kamoun M (2005) IL-27 subunits and its receptor (WSX-1) mRNAs are markedly up-regulated in inflammatory cells in the CNS during experimental autoimmune encephalomyelitis. J Neurol Sci 232:3–9PubMed

24.

Goldberg R, Wildbaum G, Zohar Y, Maor G, Karin N (2004) Suppression of ongoing adjuvant-induced arthritis by neutralizing the function of the p28 subunit of IL-27. J Immunol 173:1171–1178PubMed

25.

Hsieh CS, Macatonia SE, Tripp CS, Wolf SF, O’Garra A, Murphy KM (1993) Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260:547–549PubMed

26.

Heinzel FP, Hujer AM, Ahmed FN, Rerko RM (1997) In vivo production and function of IL-12 p40 homodimers. J Immunol 158:4381–4388PubMed

27.

Kauffman CL, Aria N, Toichi E, McCormick TS, Cooper KD, Gottlieb AB, Everitt DE, Frederick B, Zhu Y, Graham MA, Pendley CE, Mascelli MA (2004) A phase I study evaluating the safety, pharmacokinetics, and clinical response of a human IL-12 p40 antibody in subjects with plaque psoriasis. J Invest Dermatol 123(6):1037–1044 (Dec)PubMed

28.

Mannon PJ, Fuss IJ, Mayer L, Elson CO, Sandborn WJ, Present D, Dolin B, Goodman N, Groden C, Hornung RL, Quezado M, Yang Z, Neurath MF, Salfeld J, Veldman GM, Schwertschlag U, Strober W (2004) Anti-interleukin-12 antibody for active Crohn’s disease. N Engl J Med 351(20):2069–2079 (Nov 11)PubMed

29.

Kurkowska M et al (2002) Fibroblast like synoviocytes from rheumatoid arthritis patients express functional IL-15 receptor complex: endogenous IL-15 in autocrine fashion enhances cell proliferation and expression of Bcl-xL and Bcl-2. J Immunol 169:1760–1767

30.

McInnes IB, Gracie AJ (2004) Interleukin-15: a new disease cytokine target for the treatment of inflammatory diseases. Curr Opin Pharmacol 4:392–398PubMed

31.

Fehinger TA et al (2001) Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells. J Exp Med 193(2):219–231

32.

Fehinger TA, Cooper MA, Caligiuri MA (2002) Interleukin-2 and interleukin-15: immunotherapy for cancer. Cytokine Growth Factor Rev 13:169–183

33.

Basland B et al (2005) Targeting interleukin-15 in patients with rheumatoid arthritis. Arthritis Rheum 52(9):2686–2692

34.

Schluns KS, Stoklasek T, Lefrancois L (2005) The roles of interleukin-15 receptor α: trans-presentation, receptor component or both? Int J Biochem Cell Biol 37:1567–1571PubMed

35.

Dubois S et al (2002) IL-15Rα recycles and presents IL-15 in trans to neighboring cells. Immunity 17:537–547PubMed

36.

Fehinger TA et al (2001) Fatal leukemia in interleukin-15 transgenic mice. Blood Cells Mol Dis 27(1):223–230

37.

Lodolce J et al (2002) Interleukin-15 and the regulation of lymphoid homeostasis. Mol Immunol 39:537–544PubMed

38.

Ruchatz H, Leung BP, Wei XQ, McInnes IB, Liew FY (1998) Soluble IL-15 receptor α-chain administration prevents murine collagen-induced arthritis; a role for IL-15 in development of antigen-induced immunopathology. J Immunol 160:5654–5660PubMed

39.

Hsu C et al (2005) Primary human T lymphocytes engineered with a codon-optimized IL-15 gene resist cytokine withdrawal-induced apoptosis and persist long-term in the absence of exogenous cytokine. J Immunol 175:7226–7234PubMed

40.

Petrovic-Rackov L, Pejnovic N (2005) Clinical significance of IL-18, IL-15, IL-12 and TNFα measurement in rheumatoid arthritis. Clin Rheumatol 1–5 (Epub ahead of print)

41.

McInnes IB (2006) Cytokine targeting in psoriasis and psoriatic arthritis: beyond TNF-alpha. Ernst Schering Res Found Workshop 56:29–44

42.

McInnes IB, Martin R, Zimmerman-Gorska I, Nayiager S, Sun G, Patel A, Appleton B (2004) Safety and efficacy of a human monoclonal antibody to IL-15 (AMG 714) in patients with rheumatoid arthritis (RA): results from a multicenter, randomized, double-blind, placebo-controlled trial arthritis rheum (Abstract). p 527

43.

Rouvier E, Luciani MF, Mattei MG et al (1993) CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene. J Immunol 150:5445–5456PubMed

44.

Kolls JK, Linden A (2004) Interleukin-17 family members and inflammation. Immunity 21:467–476PubMed

45.

Hymowitz SG, Filvaroff EH, Yin JP et al (2001) IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding. EMBO J 20:5332–5341PubMed

46.

Moseley TA, Haudenschild DR, Rose L et al (2003) Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev 14:155–174PubMed

47.

Kramer JM, Yi L, Shen F et al (2006) Cutting edge: evidence for ligand-independent multimerization of the IL-17 receptor. J Immunol 176:711–715PubMed

48.

Awane M, Andres PG, Li DJ et al (1999) NF-kappa B-inducing kinase is a common mediator of IL-17-, TNF-alpha-, and IL-1 beta-induced chemokine promoter activation in intestinal epithelial cells. J Immunol 162:5337–5344PubMed

49.

Ferretti S, Bonneau O, Dubois GR et al (2003) IL-17, produced by lymphocytes and neutrophils, is necessary for lipopolysaccharide-induced airway neutrophilia: IL-15 as a possible trigger. J Immunol 170:2106–2112PubMed

50.

Fossiez F, Djossou O, Chomarat P et al (1996) T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med 183:2593–2603PubMed

51.

Happel KI, Zheng M, Young E et al (2003) Cutting edge: roles of Toll-like receptor 4 and IL-23 in IL-17 expression in response to Klebsiella pneumoniae infection. J Immunol 170:4432–4436PubMed

52.

Shin HC, Benbernou N, Esnault S et al (1999) Expression of IL-17 in human memory CD45RO+ T lymphocytes and its regulation by protein kinase A pathway. Cytokine 11:257–266PubMed

53.

Yao Z, Fanslow WC, Seldin MF et al (1995) Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 3:811–821PubMed

54.

Infante-Duarte C, Horton HF, Byrne MC et al (2000) Microbial lipopeptides induce the production of IL-17 in Th cells. J Immunol 165:6107–6115PubMed

55.

Harrington LE, Hatton RD, Mangan PR et al (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6:1123–1132PubMed

56.

Park H, Li Z, Yang XO et al (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6:1133–1141PubMed

57.

Hwang SY, Kim JY, Kim KW et al (2004) IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-kappaB- and PI3-kinase/Akt-dependent pathways. Arthritis Res Ther 6:R120–R128PubMed

58.

Jovanovic DV, Di Battista JA, Martel-Pelletier J et al (1998) IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. J Immunol 160:3513–3521PubMed

59.

Ryu S, Lee JH, Kim SI (2006) IL-17 increased the production of vascular endothelial growth factor in rheumatoid arthritis synoviocytes. Clin Rheumatol 25:16–20PubMed

60.

Chabaud M, Garnero P, Dayer JM et al (2000) Contribution of interleukin 17 to synovium matrix destruction in rheumatoid arthritis. Cytokine 12:1092–1099PubMed

61.

Shalom-Barak T, Quach J, Lotz M (1998) Interleukin-17-induced gene expression in articular chondrocytes is associated with activation of mitogen-activated protein kinases and NF-kappaB. J Biol Chem 273:27467–27473PubMed

62.

Kotake S, Udagawa N, Takahashi N et al (1999) IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 103:1345–1352PubMed

63.

Teunissen MB, Koomen CW, de Waal Malefyt R et al (1998) Interleukin-17 and interferon-gamma synergize in the enhancement of proinflammatory cytokine production by human keratinocytes. J Invest Dermatol 111:645–649PubMed

64.

Chabaud M, Durand JM, Buchs N et al (1999) Human interleukin-17: a T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum 42:963–970PubMed

65.

Ziolkowska M, Koc A, Luszczykiewicz G et al (2000) High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism. J Immunol 164:2832–2838PubMed

66.

Murphy CA, Langrish CL, Chen Y et al (2003) Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 198:1951PubMed

67.

Lubberts E, Joosten LA, Oppers B et al (2001) IL-1-independent role of IL-17 in synovial inflammation and joint destruction during collagen-induced arthritis. J Immunol 167:1004–1013PubMed

68.

Lubberts E, Koenders MI, Oppers-Walgreen B et al (2004) Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion. Arthritis Rheum 50:650–659PubMed

69.

Nakae S, Nambu A, Sudo K et al (2003) Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol 171:6173–6177PubMed

70.

Nakamura K, Okamura H, Wada M et al (1989) Endotoxin-induced serum factor that stimulates gamma interferon production. Infect Immun 57:590–595PubMed

71.

Kato Z, Jee J, Shikano H et al (2003) The structure and binding mode of interleukin-18. Nat Struct Biol 10:966–971PubMed

72.

Ghayur T, Banerjee S, Hugunin M et al (1997) Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. Nature 386:619–623PubMed

73.

Gu Y, Kuida K, Tsutsui H et al (1997) Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme. Science 275:206–209PubMed

74.

Cheung H, Chen NJ, Cao Z et al (2005) Accessory protein-like is essential for IL-18-mediated signaling. J Immunol 174:5351–5357PubMed

75.

Gracie JA, Robertson SE, McInnes IB (2003) Interleukin-18. J Leukoc Biol 73:213–224PubMed

76.

Conti B, Jahng JW, Tinti C et al (1997) Induction of interferon-gamma inducing factor in the adrenal cortex. J Biol Chem 272:2035–2037PubMed

77.

Gracie JA, Forsey RJ, Chan WL et al (1999) A proinflammatory role for IL-18 in rheumatoid arthritis. J Clin Invest 104:1393–1401PubMed

78.

Matsui K, Yoshimoto T, Tsutsui H et al (1997) Propionibacterium acnes treatment diminishes CD4+ NK1.1+ T cells but induces type I T cells in the liver by induction of IL-12 and IL-18 production from Kupffer cells. J Immunol 159:97–106PubMedCrossRef

79.

Pizarro TT, Michie MH, Bentz M et al (1999) IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn’s disease: expression and localization in intestinal mucosal cells. J Immunol 162:6829–6835PubMed

80.

Prinz M, Hanisch UK (1999) Murine microglial cells produce and respond to interleukin-18. J Neurochem 72:2215–2218PubMed

81.

Stoll S, Jonuleit H, Schmitt E et al (1998) Production of functional IL-18 by different subtypes of murine and human dendritic cells (DC): DC-derived IL-18 enhances IL-12-dependent Th1 development. Eur J Immunol 28:3231–3239PubMed

82.

Stoll S, Muller G, Kurimoto M et al (1997) Production of IL-18 (IFN-gamma-inducing factor) messenger RNA and functional protein by murine keratinocytes. J Immunol 159:298–302PubMed

83.

Udagawa N, Horwood NJ, Elliott J et al (1997) Interleukin-18 (interferon-gamma-inducing factor) is produced by osteoblasts and acts via granulocyte/macrophage colony-stimulating factor and not via interferon-gamma to inhibit osteoclast formation. J Exp Med 185:1005–1012PubMed

84.

Afkarian M, Sedy JR, Yang J et al (2002) T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nat Immunol 3:549–557PubMed

85.

Gerdes N, Sukhova GK, Libby P et al (2002) Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis. J Exp Med 195:245–257PubMed

86.

Gutzmer R, Langer K, Mommert S et al (2003) Human dendritic cells express the IL-18R and are chemoattracted to IL-18. J Immunol 171:6363–6371PubMed

87.

Hyodo Y, Matsui K, Hayashi N et al (1999) IL-18 up-regulates perforin-mediated NK activity without increasing perforin messenger RNA expression by binding to constitutively expressed IL-18 receptor. J Immunol 162:1662–1668PubMed

88.

Leung BP, Culshaw S, Gracie JA et al (2001) A role for IL-18 in neutrophil activation. J Immunol 167:2879–8686PubMed

89.

Wittmann M, Purwar R, Hartmann C et al (2005) Human keratinocytes respond to interleukin-18: implication for the course of chronic inflammatory skin diseases. J Invest Dermatol 124:1225–1233PubMed

90.

Dao T, Mehal WZ, Crispe IN (1998) IL-18 augments perforin-dependent cytotoxicity of liver NK-T cells. J Immunol 161:2212–2217

91.

Micallef MJ, Ohtsuki T, Kohno K et al (1996) Interferon-gamma-inducing factor enhances T helper 1 cytokine production by stimulated human T cells: synergism with interleukin-12 for interferon-gamma production. Eur J Immunol 26:1647–1651PubMed

92.

Munder M, Mallo M, Eichmann K et al (1998) Murine macrophages secrete interferon gamma upon combined stimulation with interleukin (IL)-12 and IL-18: a novel pathway of autocrine macrophage activation. J Exp Med 187:2103–2108PubMed

93.

Okamura H, Tsutsi H, Komatsu T et al (1995) Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 378:88–91PubMed

94.

Yoshimoto T, Takeda K, Tanaka T et al (1998) IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN-gamma production. J Immunol 161:3400–3407PubMed

95.

Park CC, Morel JC, Amin MA et al (2001) Evidence of IL-18 as a novel angiogenic mediator. J Immunol 167:1644–1653PubMed

96.

Wei XQ, Leung BP, Arthur HM et al (2001) Reduced incidence and severity of collagen-induced arthritis in mice lacking IL-18. J Immunol 166:517–521PubMed

97.

Banda NK, Vondracek A, Kraus D et al (2003) Mechanisms of inhibition of collagen-induced arthritis by murine IL-18 binding protein. J Immunol 170:2100–2105PubMed

98.

Plater-Zyberk C, Joosten LA, Helsen MM et al (2001) Therapeutic effect of neutralizing endogenous IL-18 activity in the collagen-induced model of arthritis. J Clin Invest 108:1825–1832PubMed

99.

Smeets RL, van de Loo FA, Arntz OJ et al (2003) Adenoviral delivery of IL-18 binding protein C ameliorates collagen-induced arthritis in mice. Gene Ther 10:1004–1011PubMed

100.

Miranda LA, Fischer RG, Sztajnbok FR et al (2005) Increased interleukin-18 in patients with juvenile idiopathic arthritis and early attachment loss. J Periodontol 76:75–82PubMed

101.

Maeno N, Takei S, Nomura Y et al (2002) Highly elevated serum levels of interleukin-18 in systemic juvenile idiopathic arthritis but not in other juvenile idiopathic arthritis subtypes or in Kawasaki disease: comment on the article by Kawashima et al. Arthritis Rheum 46:2539–2541, author reply pp. 2541–2542PubMed

102.

Naik SM, Cannon G, Burbach GJ et al (1999) Human keratinocytes constitutively express interleukin-18 and secrete biologically active interleukin-18 after treatment with pro-inflammatory mediators and dinitrochlorobenzene. J Invest Dermatol 113:766–772PubMed

103.

Arican O, Aral M, Sasmaz S et al (2005) Serum levels of TNF-alpha, IFN-gamma, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psoriasis and correlation with disease severity. Mediators Inflamm 2005:273–279PubMed

104.

Companjen A, van der Wel L, van der Fits L et al (2004) Elevated interleukin-18 protein expression in early active and progressive plaque-type psoriatic lesions. Eur Cytokine Netw 15:210–216PubMed

105.

Rothe H, Hausmann A, Casteels K et al (1999) IL-18 inhibits diabetes development in nonobese diabetic mice by counterregulation of Th1-dependent destructive insulitis. J Immunol 163:1230–1236PubMed

106.

Rothe H, Jenkins NA, Copeland NG et al (1997) Active stage of autoimmune diabetes is associated with the expression of a novel cytokine, IGIF, which is located near Idd2. J Clin Invest 99:469–474PubMedCrossRef

107.

Jander S, Stoll G (1998) Differential induction of interleukin-12, interleukin-18, and interleukin-1beta converting enzyme mRNA in experimental autoimmune encephalomyelitis of the Lewis rat. J Neuroimmunol 91:93–99PubMed

108.

Wildbaum G, Youssef S, Grabie N et al (1998) Neutralizing antibodies to IFN-gamma-inducing factor prevent experimental autoimmune encephalomyelitis. J Immunol 161:6368–6374PubMed

109.

Balashov KE, Rottman JB, Weiner HL et al (1999) CCR5(+) and CXCR3(+) T cells are increased in multiple sclerosis and their ligands MIP-1alpha and IP-10 are expressed in demyelinating brain lesions. Proc Natl Acad Sci U S A 96:6873–6878PubMed

Title: Interleukin-12 to interleukin ‘infinity’: the rationale for future therapeutic cytokine targeting
Authors: E. J. R. Anderson
M. A. McGrath
T. Thalhamer
I. B. McInnes
Publication date: 01-06-2006
Publisher: Springer-Verlag
Published in: Seminars in Immunopathology / Issue 4/2006
Print ISSN: 1863-2297
Electronic ISSN: 1863-2300
DOI: https://doi.org/10.1007/s00281-006-0011-x

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