Ab

Fig. 6. Histological examination of the skin in IL-1Ra-//- mice. A Hematoxylin and eosin staining of the ear pinna of a normal 20-week-old WT mouse. B An affected IL-1Ra-//- mouse at 20 weeks of age. The epidermis becomes thickened and hypertrophic associated with hyperkeratosis of the skin. Massive infiltration of neutrophils into the epidermis and dermis are observed in IL-1Ra-//- mouse

Fig. 6. Histological examination of the skin in IL-1Ra-//- mice. A Hematoxylin and eosin staining of the ear pinna of a normal 20-week-old WT mouse. B An affected IL-1Ra-//- mouse at 20 weeks of age. The epidermis becomes thickened and hypertrophic associated with hyperkeratosis of the skin. Massive infiltration of neutrophils into the epidermis and dermis are observed in IL-1Ra-//- mouse which diseases could be induced by T cell transfer. Thus, in this case, an autoimmune process is not likely to be involved in disease pathogenesis; rather, excess IL-1 signaling directly induces inflammation within the skin.

In humans, the involvement of IL-1 in the development of psoriasis has not been elucidated completely. Some studies have indicated that IL-1a concentrations were reduced in psoriatic lesional skin as compared to nonlesional and normal skin, although IL-1^ concentrations were increased (Cooper et al. 1990; Debets et al. 1997). Our data clearly show that excess IL-1 signaling can induce psoriasis-like lesions in mice, suggesting involvement of IL-1 in the development of psoriasis in humans. In agreement with our observations, Tg mice that express IL-1a from K14 promoter in the basal epidermis also develop scaly and erythematous inflammatory skin lesions (Groves et al. 1995).

8.4.2 The Role of TNFa in the Development of Dermatitis

The development of dermatitis in IL-1Ra-/- mice was completely absent in TNFa-deficient IL-1Ra-/- mice, indicating a crucial role for TNFa in disease pathogenesis. The importance of IL-1 and TNFa were also seen in contart hypersensitivity (CHS) reactions, in which antigen-specific CD4+ T cells play a central role. 2, 4, 6-trinitrochlorobenzene (TNCB)-induced CHS was suppressed in IL-1a/|3-/- and IL-1a-/-, but not IL-1|3-/-, mice, and these responses were augmented in IL-1Ra-/-mice, suggesting an important role for IL-1a in CHS responses (Nakae et al. 2001c, 2003b). We demonstrated that the IL-1 produced by APCs of the epidermis enhances the sensitization of allergen-specific T cells and induces inflammation via TNFa production during the elicitation phase (Nakae et al. 2003b). TNFa elicits inflammatory cell infiltration in the skin through the induction of CXCLIO.

TNFa production is increased in psoriatic lesional skin as compared to nonlesional and healthy skin (Ettehadi et al. 1994). Moreover, direct correlation between TNFa concentration either at the lesional skin or serum levels and the psoriasis area severity index scores has been reported (Bonifati et al. 1994). Thus, TNFa may also be involved in the development of psoriasis in humans (Fig. 7).

Blood vessel

Epiderm is

Dermis

Blood vessel

Epiderm is

Fig. 7. Pathogenesis of dermatitis

In human psoriasis, the importance of an acquired immune response is suggested, because linkage association with MHC class I is observed (Elder et al. 1994), the dermis and the epidermis are heavily infiltrated by CD4+ T cells (Baker and Fry 1992), cyclosporin A efficiently suppresses psoriasis (Griffiths et al. 1989), and depletion of CD25+ T cells ameliorates the disease (Gottlieb et al. 1995). Furthermore, it was shown that injection of prepsoriatic skin engrafted onto scid/scid mice with CD4+ T cells induces psoriasis (Nickoloff and Wrone-Smith 1999). However, so far, no conclusive evidence has been presented for the involvement of autoimmunity in this disease. On the other hand, it has been argued that keratinocytes of psoriatics suffer from an intrinsic abnormality in the regulation of their activation by cytokines, which trigger proliferation and migration, and stimulated keratinocytes may act as initiators of an inflammatory process by means of the secretion of various cytokines able to induce the expression of cell adhesion molecules and the recruitment of inflammatory cells (Bonifati and Ameglio 1999; Shepherd et al. 2004). Our observations suggest that keratinocyte-derived pathogenesis rather than an autoimmune mechanism is involved in the development of dermatitis in IL-1Ra-/- mice. Since the infiltration of inflammatory cells is not prominent at the beginning of the disease and gradually increases, immune mechanisms may be involved at the later phase.

8.5 Conclusion

We have demonstrated that a variety of inflammatory diseases, including arthritis, aortitis, and psoriatic dermatitis, develop spontaneously in IL-1Ra-/- mice. Although excess IL-1 signaling is responsible for the development of these diseases, the pathogenic mechanisms differ significantly; both arthritis and aortitis result from the development of autoimmunity, while such autoimmune processes are not involved in the development of dermatitis. Both TNFa and IL-17 play important roles in the activation of T cells downstream of IL-1 signaling, in addition to the roles in the elicitation of inflammation. TNFa activates T cells by inducing 0X40 expression, leading to increased IL-17 production. Although IL-17 was also shown to be involved in the sensitization of T cells, the mechanism underlying this activation remains to be elucidated. Thus, both cytokines play crucial roles in the development of the autoimmunity that can cause arthritis and aortitis in this knockout mouse model. In contrast, in the case of psoriatic dermatitis, excess IL-1 signaling and TNFa signaling directly induce inflammation of the skin without the involvement of autoimmunity. Thus, IL-1 and TNFa have dual functions, the activation of T cells and the direct induction of inflammation. It is interesting that excess IL-1signaling can induce several different diseases in an animal via different mechanisms. In any case, these observations suggest that the suppression of IL-1, TNFa, and IL-17 is important in the control of inflammatory diseases; suppression of cytokine expression or action should be beneficial for the treatment of these diseases.

Acknowledgements. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and The Ministry of Health, Labour and Welfare of Japan.

References

Aarvak T, Chabaud M, Miossec P, Natvig JB (1999) IL-17 is produced by some proinflammatory Th1/Th0 cells but not by Th2 cells. J Immunol 162:12461251

Aggarwal S, Gurney AL (2002) IL-17: prototype member of an emerging cytokine family. J Leukoc Biol 71:1-8

Albanesi C, Scarponi C, Cavani A, Federici M, Nasorri F, Girolomoni G (2000) Interleukin-17 is produced by both Th1 and Th2 lymphocytes, and modulates interferon-gamma- and interleukin-4-induced activation of human keratinocytes. J Invest Dermatol 115:81-87 Baker BS, Fry L (1992) The immunology of psoriasis. Br J Dermatol 126:1-9 Bonifati C, Ameglio F (1999) Cytokines in psoriasis. Int J Dermatol 38:241-251 Bonifati C, Carducci M, Cordiali Fei P, Trento E, Sacerdoti G, Fazio M, Ameglio F (1994) Correlated increases of tumour necrosis factor-alpha, interleukin-6 and granulocyte monocyte-colony stimulating factor levels in suction blister fluids and sera of psoriatic patients - relationships with disease severity. Clin Exp Dermatol 19:383-387 Booth AD, Jayne DR, Kharbanda RK, McEniery CM, Mackenzie IS, Brown J, Wilkinson IB (2004) Infliximab improves endothelial dysfunction in systemic vasculitis: a model of vascular inflammation. Circulation 109:17181723

Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B (1975) An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A 72:3666-3670 Carter DB, Deibel MR Jr, Dunn CJ, Tomich C-SC, Laborde AL, Slightom JL, Berger AE, Bienkowski MJ, Sun FF, McEwan RN, Harris PK, Yem AW, Waszak GA, Chosay JG, Sieu LC, Hardee MM, Zurcher-Neely HA, Rear-don IM, Heinrikson RL, Truesdell SE, Shelly JA, Eessalu TE, Taylor BM, Tracey DE (1990) Purification, cloning, expression and biological characterization of an interleukin-1 receptor antagonist protein. Nature 344:633-638 Colotta F, Re F, Muzio M, Bertini R, Polentarutti N, Sironi M, Giri JG, Dower SK, Sims JE, Mantovani A (1993) Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4. Science 261:472-475 Cooper KD, Hammerberg C, Baadsgaard O, Elder JT, Chan LS, Sauder DN, Voorhees JJ, Fisher G (1990) IL-1 activity is reduced in psoriatic skin. Decreased IL-1 alpha and increased nonfunctional IL-1 beta. J Immunol 144:4593-4603

Davis P, MacIntyre DE (1992) Prostaglandins and inflammation. In: Snyder-man R (ed) Inflammation: basic principles and clinical correlates. Raven Press, New York, pp 123-137 Debets R, Hegmans JP, Croughs P, Troost RJ, Prins JB, Benner R, Prens EP (1997) The IL-1 system in psoriatic skin: IL-1 antagonist sphere of influence in lesional psoriatic epidermis. J Immunol 158:2955-2963 Dinarello CA (1991) Interleukin-1 and interleukin-1 antagonism. Blood 77:1627-1652

Dinarello CA (1996) Biologic basis for interleukin-1 in disease. Blood 87:20952147

Durum SK, Oppenheim JJ (1993) Proinflammatory cytokines and immunity. In: Paul WE (ed) Fundamental immunology, 3rd edn. Raven Press, New York, pp 801-835

Elder JT, Nair RP, Guo SW, Henseler T, Christophers E, Voorhees JJ (1994) The genetics of psoriasis. Arch Dermatol 130:216-224 Ettehadi P, Greaves MW, Wallach D, Aderka D, Camp RD (1994) Elevated tumour necrosis factor-alpha (TNF-alpha) biological activity in psoriatic skin lesions. Clin Exp Immunol 96:146-151 Feldmann M (2002) Development of anti-TNF therapy for rheumatoid arthritis.

Nat Rev Immunol 2:364-371 Feldmann M, Maini RN (2001) Anti-TNF alpha therapy of rheumatoid arthritis:

what have we learned? Annu Rev Immunol 19:163-196 Feldmann M, Brennan FM, Maini RN (1996) Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 14:397-440 Ferretti S, Bonneau O, Dubois GR, Jones CE, Trifilieff A (2003) IL-17, produced by lymphocytes and neutrophils, is necessary for lipopolysaccharide-induced airway neutrophilia: IL-15 as a possible trigger. J Immunol 170:2106-2112

Field M, Cook A, Gallagher G (1997) Immuno-localisation of tumour necrosis factor and its receptors in temporal arteritis. Rheumatol Int 17:113-118 Fowlkes JL, Winkler MK (2002) Exploring the interface between metallo-proteinase activity and growth factor and cytokine bioavailability. Cytokine Growth Factor Rev 13:277-287 Gottlieb SL, Gilleaudeau P, Johnson R, Estes L, Woodworth TG, Gottlieb AB, Krueger JG (1995) Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis. Nat Med 1:442-447 Greenfeder SA, Nunes P, Kwee L, Labow M, Chizzonite RA, Ju G (1995) Molecular cloning and characterization of a second subunit of the interleukin 1 receptor complex. J Biol Chem 270:13757-13765 Griffiths CE, Powles AV, McFadden J, Baker BS, Valdimarsson H, Fry L (1989)

Long-term cyclosporin for psoriasis. Br J Dermatol 120:253-260 Groves RW, Mizutani H, Kieffer JD, Kupper TS (1995) Inflammatory skin disease in transgenic mice that express high levels of interleukin 1 alpha in basal epidermis. Proc Natl Acad Sci U S A 92:11874-11878 Hannum CH, Wilcox CJ, Arend WP, Joslin FG, Dripps DJ, Heimdal PL, Armes LG, Sommer A, Eisenberg SP, Thompson RC (1990) Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 343:336-340

Hirsch E, Irikura VM, Paul SM, Hirsh D (1996) Functions of interleukin 1 receptor antagonist in gene knockout and overproducing mice. Proc Natl Acad Sci U S A 93:11008-11013 Horai R, Saijo S, Tanioka H, Nakae S, Sudo K, Okahara A, Ikuse T, Asano M, Iwakura Y (2000) Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. J Exp Med 191:313-320 Horai R, Nakajima A, Habiro K, Kotani M, Nakae S, Matsuki T, Nambu A, Saijo S, Kotaki H, Sudo K, Okahara A, Tanioka H, Ikuse T, Ishii N, Schwartzberg PL, Abe R, Iwakura Y (2004) TNF-alpha is crucial for the development of autoimmune arthritis in IL-1 receptor antagonist-deficient mice. J Clin Invest 114:1603-1611. Infante-Duarte C, Horton HF, Byrne MC, Kamradt T (2000) Microbial lipopep-tides induce the production of IL-17 in Th cells. J Immunol 165:6107-6115 Isoda K, Nishikawa K, Kamezawa Y, Yoshida M, Kusuhara M, Moroi M, Tada N, Ohsuzu F (2002) Osteopontin plays an important role in the development of medial thickening and neointimal formation. Circ Res 91:77-82 Iwakura Y, Tosu M, Yoshida E, Takiguchi M, Sato K, Kitajima I, Nishioka K, Yamamoto H, Takeda T, Hatanaka M, Yamamoto H, Sekiguchi T (1991) Induction of inflammatory arthropathy resembling rheumatoid arthritis in mice transgenic for HTLV-I. Science 253:1026-1028 Ji H, Pettit A, Ohmura K, Ortiz-Lopez A, Duchatelle V, Degott C, Gravallese E, Mathis D, Benoist C (2002) Critical roles for interleukin 1 and tumor necrosis factor alpha in antibody-induced arthritis. J Exp Med 196:77-85 Joosten LA, Helsen MM, Saxne T, van De Loo FA, Heinegard D, van Den Berg WB (1999) IL-1 alpha beta blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas TNF-alpha blockade only ameliorates joint inflammation. J Immunol 163:5049-5055 Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D, Kol-lias G (1991) Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J 10:4025-4031 Kennedy J, Rossi DL, Zurawski SM, Vega F Jr, Kastelein RA, Wagner JL, Hannum CH, Zlotnik A (1996) Mouse IL-17: a cytokine preferentially expressed by alpha beta TCR + CD4-CD8- T cells. J Interferon Cytokine Res 16:611-617

Kollias G, Kontoyiannis D (2002) Role of TNF/TNFR in autoimmunity: specific TNF receptor blockade may be advantageous to anti-TNF treatments. Cytokine Growth Factor Rev 13:315-321 Kolls JK, Linden A (2004) Interleukin-17 family members and inflammation. Immunity 21:467-476

Kontoyiannis D, Pasparakis M, Pizarro TT, Cominelli F, Kollias G (1999) Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10:387-398

Matsuki T, Isoda K, Horai R, Nakajima A, Aizawa Y, Suzuki K, Ohsuzu F, Iwakura Y (2005) Involvement of TNFa in the development of T cell-dependent aortitis in IL-1 receptor antagonist-deficient mice. Circulation (in press)

Moseley TA, Haudenschild DR, Rose L, Reddi AH (2003) Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev 14:155-174 Muzio M, Polentarutti N, Sironi M, Poli G, De Gioia L, Introna M, Mantovani A, Colotta F (1995) Cloning and characterization of a new isoform of the interleukin 1 receptor antagonist. J Exp Med 182:623-628 Nakae S, Asano M, Horai R, Iwakura Y (2001a) Interleukin-1 beta, but not interleukin-1 alpha, is required for T-cell-dependent antibody production. Immunology 104:402-409 Nakae S, Asano M, Horai R, Sakaguchi N, Iwakura Y (2001b) IL-1 enhances T cell-dependent antibody production through induction of CD40 ligand and 0X40 on T cells. J Immunol 167:90-97 Nakae S, Naruse-Nakajima C, Sudo K, Horai R, Asano M, Iwakura Y (2001c) IL-1 alpha, but not IL-1 beta, is required for contact-allergen-specific T cell activation during the sensitization phase in contact hypersensitivity. Int Immunol 13:1471-1478 Nakae S, Komiyama Y, Nambu A, Sudo K, Iwase M, Homma I, Sekikawa K, Asano M, Iwakura Y (2002) Antigen-specific T cell sensitization is impaired in IL-17-deficientmice, causing suppression of allergic cellular and humoral responses. Immunity 17:375-387 Nakae S, Horai R, Komiyama Y, Nambu A, Asano M, Nakane A, Iwakura Y (2003 a) The role of IL-1 in the immune system. In: Fantuzzi G (ed) Cytokine knockouts. Humana Press, Totowa, pp 99-109 Nakae S, Komiyama Y, Narumi S, Sudo K, Horai R, Tagawa Y, Sekikawa K, Matsushima K, Asano M, Iwakura Y (2003b) IL-1-induced tumor necrosis factor-alpha elicits inflammatory cell infiltration in the skin by inducing IFN-gamma-inducible protein 10 in the elicitation phase of the contact hypersensitivity response. Int Immunol 15:251-260 Nakae S, Nambu A, Sudo K, Iwakura Y (2003c) Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol 171:6173-6177

Nakae S, Saijo S, Horai R, Sudo K, Mori S, Iwakura Y (2003d) IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc Natl Acad Sci U S A 100:5986-5990 Nicklin MJ, Hughes DE, Barton JL, Ure JM, Duff GW (2000) Arterial inflammation in mice lacking the interleukin 1 receptor antagonist gene. J Exp Med 191:303-312

Nickoloff BJ, Wrone-Smith T (1999) Injection of pre-psoriatic skin with CD4+

T cells induces psoriasis. Am J Pathol 155:145-158 Pang G, Couch L, Batey R, Clancy R, Cripps A (1994) GM-CSF, IL-1 alpha, IL-1 beta, IL-6, IL-8, IL-10, ICAM-1 and VCAM-1 gene expression and cytokine production in human duodenal fibroblasts stimulated with lipopolysaccha-ride, IL-1 alpha and TNF-alpha. Clin Exp Immunol 96:437-443 Pasparakis M, Alexopoulou L, Episkopou V, Kollias G (1996) Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J Exp Med 184:1397-1411 Ramshaw AL, Roskell DE, Parums DV (1994) Cytokine gene expression in aortic adventitial inflammation associated with advanced atherosclerosis (chronic periaortitis). J Clin Pathol 47:721-727 Rouvier E, Luciani MF, Mattei MG, Denizot F, Golstein P (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 150:5445-5456

Sakaguchi M, Kato H, Nishiyori A, Sagawa K, Itoh K (1995) Characterization of CD4+ T helper cells in patients with Kawasaki disease (KD): preferential production of tumour necrosis factor-alpha (TNF-alpha) by V beta 2- or V beta 8- CD4+ T helper cells. Clin Exp Immunol 99:276-282 Shepherd J, Little MC, Nicklin MJ (2004) Psoriasis-like cutaneous inflammation in mice lacking interleukin-1 receptor antagonist. J Invest Dermatol 122:665-669

Shin HC, Benbernou N, Esnault S, Guenounou M (1999) Expression of IL-17 in human memory CD45RO+ T lymphocytes and its regulation by protein kinase A pathway. Cytokine 11:257-266 Sims JE, Gayle MA, Slack JL, Alderson MR, Bird TA, Giri JG, Colotta F, Re F, Mantovani A, Shanebeck K, Grabstein KH, Dower SK (1993) Interleukin 1 signaling occurs exclusively via the type I receptor. Proc Natl Acad Sci USA 90:6155-6159 Tanimura A, McGregor DH, Anderson HC (1986a) Calcification in atherosclerosis. I. Human studies. J Exp Pathol 2:261-273

Tanimura A, McGregor DH, Anderson HC (1986b) Calcification in atherosclerosis. II. Animal studies. J Exp Pathol 2:275-297 Thorbecke GJ, Shah R, Leu CH, Kuruvilla AP, Hardison AM, Palladino MA (1992) Involvement of endogenous tumor necrosis factor alpha and transforming growth factor beta during induction of collagen type II arthritis in mice. Proc Natl Acad Sci U S A 89:7375-7379 Tocci MJ, Schmidt JA (1997) Interleukin-1: structure and function. In: Remick DG, Friedland JS (eds) Cytokines in health and disease, 2nd edn. Marcel Dekker, New York, pp 1-27 Van Kooten C, Banchereau J (2000) CD40-CD40 ligand. J Leukoc Biol 67:2-17 Weinberg AD (2002) 0X40: Targeted immunotherapy - implications for tempering autoimmunity and enhancing vaccines. Trends Immunol 23:102-109 Werman A, Werman-Venkert R, White R, Lee JK, Werman B, Krelin Y, Voronov E, Dinarello CA, Apte RN (2004) The precursor form of IL-1a is an intracrine proinflammatory activator of transcription. Proc Nat Acad Sci USA 101:2434-2439 Yao Z, Fanslow WC, Seldin MF, Rousseau AM, Painter SL, Comeau MR, Cohen JI, Spriggs MK (1995a) Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 3:811-821 Yao Z, Painter SL, Fanslow WC, Ulrich D, Macduff BM, Spriggs MK, Ar-mitage RJ (1995b) Human IL-17: a novel cytokine derived from T cells. J Immunol 155:5483-5486 Ye P, Rodriguez FH, Kanaly S, Stocking KL, Schurr J, Schwarzenberger P, Oliver P, Huang W, Zhang P, Zhang J, Shellito JE, Bagby GJ, Nelson S, Charrier K, Peschon JJ, Kolls JK (2001) Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J Exp Med 194:519-527

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