Therapeutic effects of interleukin-6 blockade in a murine model of polymyositis that does not require interleukin-17A.
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.


CONCLUSIONS
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.
Okiyama
Naoko
N
Department of Medicine and Rheumatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Sugihara
Takahiko
T
Iwakura
Yoichiro
Y
Yokozeki
Hiroo
H
Miyasaka
Nobuyuki
N
Kohsaka
Hitoshi
H
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D004195:Disease Models, Animal; D020381:Interleukin-17 / Q000276:immunology*; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D017285:Polymyositis / Q000276:immunology / Q000378:metabolism*; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors / Q000276:immunology; D000093242:Interleukin-6 Inhibitors
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D020381:Interleukin-17; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D000093242:Interleukin-6 Inhibitors; C098680:Il17a protein, mouse