Synergistic effects of cyclic strain and Th1-like cytokines on tenascin-C production by rheumatic aortic valve interstitial cells.
Tenascin-C (TN-C) is a key component of extracellular matrix (ECM) and its expression process is poorly understood during rheumatic heart valvular disease (RHVD). In this study, we found that interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha and TN-C concentrations in patients with RHVD were significantly higher than in normal controls. More IFN-gamma receptors and TNF receptors were found being expressed on rheumatic aortic valves interstitial cells than on non-rheumatic ones and their expression was patients' sera dependent. Antibodies neutralizing IFN-gamma or TNF-alpha could attenuate patients' sera-induced TN-C transcription by isolated rheumatic aortic valves interstitial cells. By application with different protein kinase inhibitors, we found that combined with cyclic strain, TNF-alpha and IFN-gamma induced TN-C transcription through the RhoA/ROCK signalling pathway. At the same time, p38 mitogen-activated protein kinase was involved in TNF-alpha and IFN-gamma induced TN-C transcription. TNF-alpha also increased TN-C mRNA level by additional PKC and ERK 1/2 activation. Our finding revealed a new insight into ECM remodelling during RHVD pathogenesis and new mechanisms involved in the clinical anti-IFN-gamma and anti-TNF-alpha therapy.
Jiang
L
L
Department of Cardiac Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Wei
X F
XF
Yi
D H
DH
Xu
P
P
Liu
H
H
Chang
Q
Q
Yang
S M
SM
Li
Z F
ZF
Gao
H B
HB
Hao
G J
GJ
D000328:Adult; D001021:Aortic Valve / Q000002:abnormalities / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology*; D005260:Female; D006353:Heart-Assist Devices; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D017471:Receptors, Interferon / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012214:Rheumatic Heart Disease / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D013314:Stress, Mechanical; D019063:Tenascin / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D015533:Transcriptional Activation / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D055815:Young Adult; D000096743:Interferon gamma Receptor
D016207:Cytokines; D007371:Interferon-gamma; D012333:RNA, Messenger; D017471:Receptors, Interferon; D018124:Receptors, Tumor Necrosis Factor; D019063:Tenascin; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor