Arid5a exacerbates IFN-γ-mediated septic shock by stabilizing T-bet mRNA.
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-γ, IL-6, and TNF-α, than WT mice in response to LPS. Arid5a deficiency resulted in decreased levels of IFN-γ 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-γ dependent endotoxic shock mouse model. Thus, regulation of IFN-γ 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-γ and IL-6 significantly recovered the mice from endotoxic shock. Taken together, we conclude that Arid5a regulates the augmentation of IL-6 and IFN-γ in response to LPS, which possibly works synergistically for amplification of various other cytokines that ultimately cause the development of septic shock in mice.
Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
Mohammad Mahabub-Uz
MM
Zaman
Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
Kazuya
K
Masuda
Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
Kishan Kumar
KK
Nyati
Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
Praveen Kumar
PK
Dubey
Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
Barry
B
Ripley
Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
Kai
K
Wang
Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
Jaya Prakash
JP
Chalise
Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
Mitsuru
M
Higa
Biological Sciences Department, College of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia.
Hamza
H
Hanieh
Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan; kishimoto@ifrec.osaka-u.ac.jp.
Tadamitsu
T
Kishimoto
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002469:Cell Separation; D017124:Conserved Sequence / Q000235:genetics; D016207:Cytokines / Q000097:blood; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D008070:Lipopolysaccharides; D008213:Lymphocyte Activation; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D009690:Nucleic Acid Conformation; D011425:Propionibacterium acnes / Q000502:physiology; D011485:Protein Binding; D020871:RNA Stability / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012772:Shock, Septic / Q000097:blood / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D000098815:T-bet Transcription Factor
D020413:3' Untranslated Regions; C582683:Arid5a protein, mouse; D016207:Cytokines; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D007371:Interferon-gamma
Arid5a; IFN-γ; IL-6; T-bet; septic shock
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