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Early inhibition of tumor necrosis factor‐α and interleukin‐6 in muscle tissue as a therapy for dystrophinopathy in mdx mice
Author(s) -
Arahata Hajime,
Ohyagi Yasumasa,
Iinuma Kyoko M.,
Tanaka Masahito,
Tateishi Takahisa,
Yamasaki Ryo,
Matsushita Takuya,
Kira Junichi
Publication year - 2014
Publication title -
clinical and experimental neuroimmunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.297
H-Index - 15
ISSN - 1759-1961
DOI - 10.1111/cen3.12111
Subject(s) - mdx mouse , proinflammatory cytokine , chemokine , tumor necrosis factor alpha , cytokine , interleukin , medicine , inflammation , endocrinology , dystrophin , immunology , chemistry , pathology , skeletal muscle
Abstract Objective Pro‐inflammatory cytokines can exacerbate muscle fiber damage in dystrophinopathy. The aim of the present study was to identify cytokine/chemokine alterations in the muscle tissues of mdx mice, a model of dystrophinopathy, and the beneficial effects of anti‐proinflammatory cytokine therapy. Methods A total of 23 cytokines and chemokines were quantitatively measured in muscle tissues from mdx mice by fluorescent bead‐based immunoassay. The mdx mice were treated with anti‐tumor necrosis factor‐α ( TNF ‐α) and anti‐interleukin‐6 ( IL ‐6) drugs, and their physical condition was evaluated by Rotarod and muscle damage by histopathological analysis. Results Levels of TNF ‐α and IL ‐6 were elevated at 14 days (P14), before a transient increase of macrophage and neutrophil‐activating pro‐inflammatory cytokines/chemokines, such as C‐C motif ligand 2 ( CCL 2), CCL 4 and KC (mouse C‐X‐C motif ligand 8 homolog), at P20. Administration of an anti‐ TNF ‐α drug (etanercept) and an anti‐ IL ‐6 receptor antibody ( MR 16‐1) from P7 improved physical performance, and reduced both the area of basophilic fibers that indicated degenerating/regenerating fibers and CD 68‐positive macrophage infiltration. Initiating therapy at P7 inhibited the elevation of CCL 2, CCL 4 and KC more effectively than at P13. Conclusions The early administration of anti‐ TNF ‐α and anti‐ IL ‐6 drugs attenuated muscle fiber degeneration in a mouse model of dystrophinopathy.