Calcium/Calmodulin-Dependent Protein Kinase IV (CaMKIV) Mediates Acute Skeletal Muscle Inflammatory Response
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ORIGINAL ARTICLE
Calcium/Calmodulin-Dependent Protein Kinase IV (CaMKIV) Mediates Acute Skeletal Muscle Inflammatory Response DanDan Shi,1 RuiCai Gu,1 YaFeng Song,2 MaoChao Ding,1 Tao Huang,1 MengXia Guo,1 JiangWei Xiao,1 WenHua Huang,1 and Hua Liao 1,3
Abstract—The objective of this study is to investigate the role of Calmodulin-dependent protein
kinase IV (CaMKIV) in Cardiotoxin (CTX)-induced mice muscle inflammation. CTX injection i.m. was performed to induce B6 mice acute tibialis anterior (TA) muscle injury. The mice were then injected i.p. with the recombinant CaMKIV protein or its antagonist KN-93. Immunoblotting was used to assess Calmodulin (CaM) and CaMKIV levels. Immunofluorescence was used to detect intramuscular infiltration or major histocompatibility complex (MHC)-I expression in damaged muscle. The extent of infiltration was evaluated by fluorescent intensity analysis. Cytokines/chemokines levels were determined by qPCR. CaMKIV gene knockdown in C2C12 cells was performed in order to evaluate the effects of CaMKIV on immuno-behavior of muscle cells. CTX administration induced a strong up-regulation of CaM and p-CaMKIV levels in infiltrated mononuclear cells and regenerated myofibers. In vivo adding of the recombinant CaMKIV protein enhanced intramuscular infiltration of monocytes/macrophages in damaged muscle and increased the number of proinflammatory Ly-6C+F4/80+ macrophage cells. CaMKIV DanDan Shi, RuiCai Gu and YaFeng Song contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10753-017-0678-2) contains supplementary material, which is available to authorized users. 1
Department of Anatomy, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, School of Basic Medical Science, Southern Medical University, No.1838, GuangZhou Avenue North, GuangZhou, 510515, China 2 Perelman School of Medicine and Pennsylvania Muscle Institute, University of Pennsylvania, 422 Curie Blvd. Rm 715, Philadelphia, PA 19104, USA 3 To whom correspondence should be addressed at Department of Anatomy, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, School of Basic Medical Science, Southern Medical University, No.1838, GuangZhou Avenue North, GuangZhou, 510515, China. E-mail: [email protected]
Antigen-presenting cells; Ca2+/CaM, Calcium/Calmodulin; CaMKIV, CaM-dependent protein kinase IV; CaMKKs, CaM-dependent protein kinase kinases; CTX, Cardiotoxin; DCs, Dendritic cells; GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; TA, Tibialis anterior muscle; TLRs, Toll-like receptors; Tregs, Regulatory T cells Abbreviations: APCs,
0360-3997/17/0000-0001/0 # 2017 Springer Science+Business Media, LLC
Shi, Gu, Song, Ding, Huang, Guo, Xiao, Huang, and Liao protein treatment induced a striking up-regulation of mRNA levels of IL-1, IL-6, MCP-1, and MCP-3 in CD45+ cells sorted from damaged muscle; increased the infiltration of CD8+ T cells; and induced the up-regulation of MHC-I in part
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