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


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.


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