MyD88-mediated stabilization of interferon-γ-induced cytokine and chemokine mRNA

Nature Immunology 7, 375-381 (2006)

Speaker：黃炫榕                          Time：14:10 ~ 15:00, April. 26, 2006

Commentator：凌 斌 老師                 Place：Room 601

Abstract:

        The adaptor protein, MyD88, is characterized to involve in interleukin 1 receptor (IL-1R) and Toll-like receptor (TLR) signaling. It can activate downstream signal to induce the expression of proinflammatory cytokines such as tumor necrosis factor (TNF) and chemokines such as interferon-γ-inducible 10 (IP-10) that form the basic innate immune responses.However, the role of MyD88 in IFN-γ-induced signaling pathways is enigmatic in previous researches. In this study, the authors demonstrated that MyD88 is essential for interferon-γ induced signal pathway in macrophages. At first, they found that MyD88 deficiency results in TNF and IP-10 mRNA expression diminution in vitro and in vivo. In the absence of MyD88, IFN-γ-induced mRNA tends to be unstable, but transcriptional activity of TNF and IP-10 through JAK-STAT pathway is not influenced. The IFN-γ-induced stabilization of TNF and IP-10 mRNA also depends on AU-rich elements (AREs) that locate in the 3′ untranslated regions. Furthermore, IFN-γ stimulation triggers a physical association of IFN-γ receptor 1 and MyD88 and, in addition, the MyD88-dependent ARE transcriptional stabilization was mediated by sequential activation of MLK3, MKK3, and p38. These results reveal that IFN-γ induces two parallel but coordinated pathways regulating the expression of genes encoding proinflammatory molecules. IFN-γ-induced transcript synthesis is regulated by the JAK–STAT pathway, whereas transcript stabilization may be regulated by the MyD88–MLK3–p38 pathway. Thus, this paper gives MyD88 a new role beyond toll.

References:

1.          Sun, D. and A. Ding. MyD88-mediated stabilization of interferon-gamma-induced cytokine and chemokine mRNA. Nat. Immunol. 7, 375-381 (2006).

2.          Shi, S., C. Nathan, et al. MyD88 primes macrophages for full-scale activation by interferon-gamma yet mediates few responses to Mycobacterium tuberculosis.  J. Exp. Med.198, 987-997 (2003).