Activation of IKK by thymosin alpha1 requires the TRAF6 signalling pathway.
Thymosin alpha1 (T(alpha)1) is noted for its immunomodulatory activities and therapeutic potential in treatment of infectious diseases and cancer. However, the molecular mechanism of its effectiveness is not completely understood. Here, we report that T(alpha)1 induces interleukin (IL)-6 expression through the I(kappa)B kinase (IKK) and nuclear factor-(kappa)B (NF-(kappa)B) pathway. Using IKK(beta)-deficient bone-marrow-derived macrophages and mouse embryo fibroblasts (MEFs), we show that IKK(beta) is essential for IKK and NF-(kappa)B activation as well as efficient IL-6 induction. Further analysis using tumour necrosis factor receptor-associated factor 6 (TRAF6)-deficient MEFs shows that TRAF6 is crucial for activation of IKK and induction of IL-6 by Talpha1. Intriguingly, T(alpha)1 triggers protein kinase C (PKC)iota/zeta activation, which is TRAF6 dependent and involves IKK. In addition, T(alpha)1 induces the formation of a signalsome composed of TRAF6, p62 and PKC(iota)/zeta as well as IKK. Thus, our study identifies T(alpha)1 as a unique activator of the TRAF6 signal pathway and provides a cohesive interpretation of the molecular basis of the therapeutic utility of T(alpha)1.
Zhang
Ping
P
Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA.
Chan
Justin
J
Dragoi
Ana-Maria
AM
Gong
Xing
X
Ivanov
Stanimir
S
Li
Zhi-Wei
ZW
Chuang
Tsung-Hsien
TH
Chuang
Tsheng
T
Tuthill
Cynthia
C
Wan
Yinsheng
Y
Karin
Michael
M
Chu
Wen-Ming
WM
D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism; D051550:I-kappa B Kinase; D015151:Immunoblotting; D047468:Immunoprecipitation; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010957:Plasmids / Q000235:genetics; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism* / Q000502:physiology; D000077596:Thymalfasin; D013947:Thymosin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014162:Transfection; D000099221:Protein Kinase C zeta
D051550:I-kappa B Kinase; D015850:Interleukin-6; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D048029:TNF Receptor-Associated Factor 6; D000077596:Thymalfasin; D013947:Thymosin; D000099221:Protein Kinase C zeta; C496564:Chuk protein, mouse; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse