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Recent publications report that heat shock proteins (HSPs) can endow regulatory responses to the systemic immune system when administered via the mucosal route, leading to an amelioration of atherosclerosis and allergy. However, it remains poorly understood if HSP antigens exist in the luminal contents of the gastrointestinal tract and which types of HSP induce regulatory responses. Here we addressed these problems, considering that numerous gut microflora and foods are natural sources of HSPs. SDS-PAGE and immunoblotting with the anti-HSP60 antibody demonstrated the intact and degraded forms of HSP60 mainly in appendix and large intestine of the gastrointestinal tract. No reactivity with this antibody was observed for any of the luminal contents derived from germ-free animals, suggesting gut microflora to be a source of the intestinal HSPs because of lack of HSPs in animal chow diet. GroEL, a typical member of bacterial HSP60, showed a tendency to stimulate splenocytes in germ-free mice, compared to that in conventional mice, suggesting that resident commensal bacterial GroEL may stimulate HSP-reactive T cells as regulatory cells in conventional animals. Importantly, GroEL, but not mouse-derived HSP60, caused naïve T cells to differentiate into CD4⁺ CD25⁺ Foxp3⁺ T cells, indicating that the production of regulatory T cells depends on the type of HSP. Thus, HSPs derived from commensal microbes can be utilized to stimulate immunoregulatory pathways for the maintenance of intestinal homeostasis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease accompanied by severe itching and eczematous lesion. In this study, we applied an ointment containing Dermatophagoides farinae body (Dfb) extract repeatedly on the dorsal skin of NC/ Nga mice with barrier disruption to investigate the characteristics of this murine model of human AD. Following repeated topical application of Dfb ointment twice weekly for 2 weeks, the dermatitis score increased gradually, accompanied by an elevation of total immunoglobulin E level in plasma. Topical application of Dfb ointment also caused epidermal hyperplasia and accumulation of inflammatory cells in the lesional skin and increased expression of T-helper (Th) 1/Th2/Th17 cytokines in axillary lymph node cells. Furthermore, increased sprouting of intraepidermal nerve fibres was observed with an increase in the content of nerve growth factor and decrease in that of semaphorin 3A in the lesional skin. These findings suggest that the characteristics in this model were similar to those observed in patients with AD. Interestingly, it was observed for the first time that scratching behaviour increased in a biphasic fashion by topical application of Dfb ointment in addition to an increase in spontaneous scratching behaviour in this model. It is also suggested that further clarifying the underlying mechanisms of scratching behaviour in this model leads not only to elucidating the pathogenesis of AD but also to discovering novel therapeutic drugs for AD.