First Author | Zaman MM | Year | 2016 |
Journal | Proc Natl Acad Sci U S A | Volume | 113 |
Issue | 41 | Pages | 11543-11548 |
PubMed ID | 27671645 | Mgi Jnum | J:240577 |
Mgi Id | MGI:5887181 | Doi | 10.1073/pnas.1613307113 |
Citation | Zaman MM, et al. (2016) Arid5a exacerbates IFN-gamma-mediated septic shock by stabilizing T-bet mRNA. Proc Natl Acad Sci U S A 113(41):11543-11548 |
abstractText | Adenine-thymine (AT)-rich interactive domain containing protein 5a (Arid5a) is an RNA-binding protein that has been shown to play an important immune regulatory function via the stabilization of IL-6 and STAT3 mRNA. However, the role of Arid5a in the overwhelming and uncontrolled immune response that leads to septic shock is unknown. Here, we report that Arid5a-deficient mice are highly resistant to lipopolysaccharide (LPS)-induced endotoxic shock and secrete lower levels of major proinflammatory cytokines, including IFN-gamma, IL-6, and TNF-alpha, than WT mice in response to LPS. Arid5a deficiency resulted in decreased levels of IFN-gamma under Th1 cell conditions, in which T-box expressed in T cells (T-bet) mRNA expression was inhibited. Arid5a bound to the conserved stem loop structure of the 3'UTR of T-bet and stabilized its mRNA. Arid5a-deficient mice were also resistant to Propionibacterium acnes-primed LPS injection, which is considered to be a T-cell-mediated IFN-gamma dependent endotoxic shock mouse model. Thus, regulation of IFN-gamma by Arid5a via the stabilization of T-bet mRNA in Th1 cells contributes to the development of septic shock in mice. In addition, our previous study suggests that Arid5a control the IL-6 level in vivo in response to LPS by stabilization of IL-6 mRNA. We also observed that neutralization of IFN-gamma and IL-6 significantly recovered the mice from endotoxic shock. Taken together, we conclude that Arid5a regulates the augmentation of IL-6 and IFN-gamma in response to LPS, which possibly works synergistically for amplification of various other cytokines that ultimately cause the development of septic shock in mice. |