IL‐10‐induced TNF‐alpha mRNA destabilization is mediated via IL‐10 suppression of p38 MAP kinase activation and inhibition of HuR expression

Rajasingh, Johnson; Bord, Evelyn; Luedemann, Corinne; Asai, Jun; Hamada, Hiromichi; Thorne, Tina; Qin, Gangjian; Goukassian, David A.; Zhu, Yan; Losordo, Douglas W.; Kishore, Raj

doi:10.1096/fj.06-6084fje

Cited by 136 publications

(138 citation statements)

References 44 publications

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“…As previously reported that IL-10 receptor signaling destabilizes Tnfa mRNA (16,17), recombinant (r) IL-10 treatment reduced LPS-induced Tnfa mRNA levels in macrophages (Fig. S4).…”

Section: Cd40 Signaling Negatively Regulates the Stabilization Of Tnfsupporting

confidence: 76%

T cells down-regulate macrophage TNF production by IRAK1-mediated IL-10 expression and control innate hyperinflammation

Inoue¹,

Arikawa²,

Chen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Endotoxemia is caused by excessive inflammation, but the immune system has various mechanisms to avoid collateral organ damage in endotoxemia. A handful of reports have shown that innate immune responses are suppressed by the adaptive immune system. However, the molecular mechanism by which adaptive immune cells suppress innate inflammatory responses is not clear. Here, we report that T cells are shown to interact with macrophages at the early stage of enodotoxemia and to prolong survival of mice through controlling TNF and IL-10 levels by macrophage CD40 stimulation. The cross-talk between CD40 and toll-like receptor (TLR4) signaling first mediates IL-1 receptor-associated kinase 1 (IRAK1) nuclear translocation and its binding to the IL-10 gene promoter in macrophages, without interfering with the NFκB pathway. IL-10 is then detected by macrophages in an autocrine fashion to destabilize Tnfa mRNA. To induce IRAK1-mediated IL-10 expression, signals from both CD40 and TLR4 are essential. CD40 signaling induces IRAK1 sumoylation in the presence of TNF receptor-associated factor 2 (TRAF2) and intracellular isoform of osteopontin (iOPN) whereas TLR4 signaling provides IFN regulatory factor 5 (IRF5) as a chaperone for sumoylated IRAK1 nuclear translocation. Interaction of T cells with macrophages was observed in the spleen in vivo after endotoxemia induction with LPS injection. Our study demonstrates a mechanistic basis for the immunosuppressive role of macrophage CD40 in LPS endotoxemia.OPN | CD40L | CD154 | simultaneous stimulation | T cell migration

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“…As previously reported that IL-10 receptor signaling destabilizes Tnfa mRNA (16,17), recombinant (r) IL-10 treatment reduced LPS-induced Tnfa mRNA levels in macrophages (Fig. S4).…”

Section: Cd40 Signaling Negatively Regulates the Stabilization Of Tnfsupporting

confidence: 76%

T cells down-regulate macrophage TNF production by IRAK1-mediated IL-10 expression and control innate hyperinflammation

Inoue¹,

Arikawa²,

Chen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…An explanation for this finding may be the counter-regulation between IL-10 and TNF-α. IL-10 production requires the initial presence of TNF-α but IL-10 regulates the stability of TNF-α mRNA [16]. Inconsistent inhibition of suppression, using neutralizing anti-IL-10, may be due to IL-10 gene polmorphisms that relate to high/low IL-10 production [17].…”

Section: Discussionmentioning

confidence: 99%

Defective CD8+CD28− regulatory T cell suppressor function in rheumatoid arthritis is restored by tumour necrosis factor inhibitor therapy

Ceeraz

Hall

Choy

et al. 2013

Clinical and Experimental Immunology

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“…We and others and have shown previously that members of the MAPK family are involved in modulating mRNA stability and/or translation of several pro-inflammatory genes (Kochanek et al, 2012;Rajasingh et al, 2006). Studies have shown that activation (i.e.…”

Section: Aza+tsa Treatment Suppresses Hur Expression and P38mapk Actimentioning

confidence: 93%

Epigenetic modifiers reduce inflammation and modulate macrophage phenotype during endotoxemia-induced acute lung injury

Jayakumar

Samanta

Rajasingh

et al. 2015

Journal of Cell Science

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Acute lung injury (ALI) during sepsis is characterized by bilateral alveolar infiltrates, lung edema, and respiratory failure. Here, we examined the efficacy of DNA methyl transferase (DNMT) inhibitor Aza (5-Aza 2-deoxycytidine), histone deacetylase (HDAC) inhibitor TSA (Trichostatin A), and combination therapy (Aza+TSA) in protection of ALI. In LPS-induced mouse ALI, post-treatment with a single dose of Aza+TSA showed a substantial attenuation of adverse lung histopathological changes, and inflammations. Importantly, these protective effects were due to significant macrophage phenotypic changes observed in LPS-stimulated macrophages treated with Aza+TSA as compared with untreated LPS-induced macrophages or LPS-stimulated macrophages treated with either drug alone. Further, we observed significantly lower levels of pro-inflammatory molecules and higher levels of anti-inflammatory molecules in LPS-induced macrophages treated with Aza+TSA than in LPS-induced macrophages treated with either drug alone. The protection was ascribed to dual effects by an inhibition of MAPK-HuR-TNF and activation of STAT3-Bcl2 pathways. Combinatorial treatment with Aza+TSA reduces inflammation and promotes an anti-inflammatory M2 macrophage phenotype in ALI. This finding gives further evidence that the epigenetic treatment has a therapeutic potential for patients with sepsis.

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IL‐10‐induced TNF‐alpha mRNA destabilization is mediated via IL‐10 suppression of p38 MAP kinase activation and inhibition of HuR expression

Cited by 136 publications

References 44 publications

T cells down-regulate macrophage TNF production by IRAK1-mediated IL-10 expression and control innate hyperinflammation

T cells down-regulate macrophage TNF production by IRAK1-mediated IL-10 expression and control innate hyperinflammation

Defective CD8+CD28− regulatory T cell suppressor function in rheumatoid arthritis is restored by tumour necrosis factor inhibitor therapy

Epigenetic modifiers reduce inflammation and modulate macrophage phenotype during endotoxemia-induced acute lung injury

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