OBJECTIVE: To explore new molecular targets in the treatment of polymyositis (PM) by examining a recently established murine model of PM, C protein-induced myositis (CIM), for involvement of an interleukin-6 (IL-6)/IL-17A pathway. METHODS: CIM was induced by immunizing wild-type mice as well as IL-6-null and IL-17A-null C57BL/6 mice with recombinant mouse skeletal C protein fragments. Some mice were treated with anti-IL-6 receptor (anti-IL-6R) monoclonal antibodies or control antibodies. Muscle tissue samples were examined histologically and immunohistochemically. RESULTS: The syngeneic C protein fragments successfully induced inflammation in the skeletal muscles of wild-type mice. IL-6 was expressed by mononuclear cells, especially in macrophages, infiltrating in the muscles. IL-6-null mice developed myositis with significantly lower incidence and milder severity than wild-type mice. In contrast, IL-17A-null mice were as susceptible to CIM as wild-type mice. Intraperitoneal administration of anti-IL-6R monoclonal antibodies, but not of control monoclonal antibodies, ameliorated CIM both preventively and therapeutically. CONCLUSION: Our findings indicate that IL-6 is critically involved in the development of CIM. Although many other autoimmune models require IL-6 for differentiation of pathogenic T cells producing IL-17A, IL-17A was dispensable in CIM. Nevertheless, treatment with anti-IL-6R antibodies was effective. IL-6 blockade is potentially a new approach to the treatment of autoimmune myositis, via processes distinct from interference in the IL-6/IL-17A pathway.
OBJECTIVE: To explore new molecular targets in the treatment of polymyositis (PM) by examining a recently established murine model of PM, C protein-induced myositis (CIM), for involvement of an interleukin-6 (IL-6)/IL-17A pathway. METHODS:CIM was induced by immunizing wild-type mice as well as IL-6-null and IL-17A-null C57BL/6 mice with recombinant mouse skeletal C protein fragments. Some mice were treated with anti-IL-6 receptor (anti-IL-6R) monoclonal antibodies or control antibodies. Muscle tissue samples were examined histologically and immunohistochemically. RESULTS: The syngeneic C protein fragments successfully induced inflammation in the skeletal muscles of wild-type mice. IL-6 was expressed by mononuclear cells, especially in macrophages, infiltrating in the muscles. IL-6-null mice developed myositis with significantly lower incidence and milder severity than wild-type mice. In contrast, IL-17A-null mice were as susceptible to CIM as wild-type mice. Intraperitoneal administration of anti-IL-6R monoclonal antibodies, but not of control monoclonal antibodies, ameliorated CIM both preventively and therapeutically. CONCLUSION: Our findings indicate that IL-6 is critically involved in the development of CIM. Although many other autoimmune models require IL-6 for differentiation of pathogenic T cells producing IL-17A, IL-17A was dispensable in CIM. Nevertheless, treatment with anti-IL-6R antibodies was effective. IL-6 blockade is potentially a new approach to the treatment of autoimmune myositis, via processes distinct from interference in the IL-6/IL-17A pathway.