Inhibition of IL-2 inducible T-cell kinase alleviates T-cell activation and murine myocardial inflammation associated with CVB3 infection.
BACKGROUND
Coxsackievirus B3 (CVB3) infection causes myocarditis, pancreatitis, and aseptic meningitis. Targeting antigen-specific T cell reactions might be a promising way to alleviate the inflammatory response induced by CVB3 infection. IL-2-inducible T-cell kinase (ITK), a member of Tec kinase family expressed mainly in T cells, plays an important role in the activation of T cells. The role of ITK in viral myocarditis induced by CVB3 has not been documented.


METHODS
In this study, we inhibited the ITK expression in Jurkat cells, primary human peripheral blood mononuclear cells (PBMC), and mouse splenocytes by ITK-specific siRNA. The inhibition efficiently suppressed cell proliferation (P<0.05) and T-cell related cytokine secretion (P<0.05). In order to inhibit ITK in vivo, the pGCSIL plasmid containing short hairpin RNAs targeting ITK was constructed and transduced into mice infected with CVB3. ITK-inhibited mice showed reduced cell proliferation (3, 5, and 7 days post-challenge, P<0.05) as well as CD4+ and CD8+ T cells (5 days post-challenge, P<0.05). The altered production of inflammatory cytokines alleviated pathologic heart damage and improved mice survival rate (P<0.05).


CONCLUSIONS
ITK played an important role in the T cell development and represented a new target for the modulation of T-cell-mediated inflammatory response by CVB3 infection.
Molecular Immunology Laboratory, Capital Institute of Pediatrics, Beijing 100020, China.
Feng
F
He
Molecular Immunology Laboratory, Capital Institute of Pediatrics, Beijing 100020, China.
Hailan
H
Yao
Molecular Immunology Laboratory, Capital Institute of Pediatrics, Beijing 100020, China.
Zonghui
Z
Xiao
Medical Department, Aerospace 731 Hospital, Beijing 100074, China.
Jisheng
J
Han
Pathology Laboratory, Capital Institute of Pediatrics, Beijing 100020, China.
Jizhen
J
Zou
Molecular Immunology Laboratory, Capital Institute of Pediatrics, Beijing 100020, China. Electronic address: zheweiliu@163.com.
Zhewei
Z
Liu
D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D003384:Coxsackievirus Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D029822:Enterovirus B, Human / Q000276:immunology* / Q000502:physiology; D005434:Flow Cytometry; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000235:genetics / Q000276:immunology* / Q000821:virology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D034622:RNA Interference / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D016207:Cytokines; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase
Coxsackievirus B3; ITK; Myocarditis; RNAi