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TRAF6 mediates IL-1?/LPS-induced suppression of TGF-? signaling through its interaction with the type III TGF-? receptor.

ABSTRACT: Transforming growth factor-?1 (TGF-?1) is an important anti-inflammatory cytokine that modulates and resolves inflammatory responses. Recent studies have demonstrated that inflammation enhances neoplastic risk and potentiates tumor progression. In the evolution of cancer, pro-inflammatory cytokines such as IL-1? must overcome the anti-inflammatory effects of TGF-? to boost pro-inflammatory responses in epithelial cells. Here we show that IL-1? or Lipopolysaccharide (LPS) suppresses TGF-?-induced anti-inflammatory signaling in a NF-?B-independent manner. TRAF6, a key molecule in IL-1? signaling, mediates this suppressive effect through interaction with the type III TGF-? receptor (T?RIII), which is TGF-?-dependent and requires type I TGF-? receptor (T?RI) kinase activity. T?RI phosphorylates T?RIII at residue S829, which promotes the TRAF6/T?RIII interaction and consequent sequestration of T?RIII from the T?RII/T?RI complex. Our data indicate that IL-1? enhances the pro-inflammatory response by suppressing TGF-? signaling through TRAF6-mediated sequestration of T?RIII, which may be an important contributor to the early stages of tumor progression.

SUBMITTER: Lim S

PROVIDER: S-EPMC3299683 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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TRAF6 mediates IL-1β/LPS-induced suppression of TGF-β signaling through its interaction with the type III TGF-β receptor.

Lim Seunghwan S Bae Eunjin E Kim Hae-Suk HS Kim Tae-Aug TA Byun Kyunghee K Kim Byungchul B Hong Suntaek S Im Jong Pil JP Yun Chohee C Lee Bona B Lee Bonghee B Park Seok Hee SH Letterio John J Kim Seong-Jin SJ

PloS one 20120312 3

Transforming growth factor-β1 (TGF-β1) is an important anti-inflammatory cytokine that modulates and resolves inflammatory responses. Recent studies have demonstrated that inflammation enhances neoplastic risk and potentiates tumor progression. In the evolution of cancer, pro-inflammatory cytokines such as IL-1β must overcome the anti-inflammatory effects of TGF-β to boost pro-inflammatory responses in epithelial cells. Here we show that IL-1β or Lipopolysaccharide (LPS) suppresses TGF-β-induced ...[more]

PMID: 22427868

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Project description:BACKGROUND:microRNA-146a-5p (miRNA-146a-5p) is a key molecule in the negative regulation pathway of TLRs and IL-1 receptor (TIR) signaling. Our recent study demonstrated that MyD88-dependent signaling pathway of TIR in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH) plays a role in peripheral nerve injury-induced neuropathic pain. However, it was not clear whether and how miRNA-146a-5p regulates the TIR pathway of DRG and SDH in the development of neuropathic pain. METHODS:The sciatic nerve chronic constriction injury (CCI) model of rat was used to induce chronic neuropathic pain. The levels and cellular distribution of miRNA-146a-5p were detected with quantitative real-time PCR (qPCR) and fluorescent in situ hybridization (FISH). The RNA level, protein level, and cellular distribution of IRAK1 and TRAF6 that is targeted by miRNA-146a-5p were detected with qPCR, western blot, and immunofluorescent. The pain-related behavioral effect of miRNA-146a-5p was accessed after intrathecal administration. Mechanical stimuli and radiant heat were used to evaluate mechanical allodynia and thermal hyperalgesia. RESULTS:We found that the level of miRNA-146a-5p significantly increased in L4-L6 DRGs and SDH after CCI surgery; meanwhile, the protein level of IRAK1 and TRAF6 in DRGs was significantly increased after CCI. Intrathecal injection of miR146a-5p agomir or miRNA-146a-5p antagomir regulates miRNA-146a-5p level of L4-L6 DRGs and SDH. We found that intrathecal injection of miR146a-5p agomir can alleviate mechanical and thermal hyperalgesia in CCI rats and reverse the upregulation of IRAK1 and TRAF6 of L4-L6 DRGs and SDH induced by CCI. We furthermore found that intrathecal injection of miRNA-146a-5p antagomir can exacerbate the mechanical and thermal pain-related behavior of CCI rats and meanwhile increase IRAK1 and TRAF6 of L4-L6 DRGs and SDH expression even further. CONCLUSIONS:miRNA-146a-5p of DRG and SDH can modulate the development of CCI-induced neuropathic pain through inhibition of IRAK1 and TRAF6 in the TIR signaling pathway. Hence, miRNA-146a-5p may serve as a potential therapeutic target for neuropathic pain.

Dataset Information

TRAF6 mediates IL-1?/LPS-induced suppression of TGF-? signaling through its interaction with the type III TGF-? receptor.

Publications

TRAF6 mediates IL-1β/LPS-induced suppression of TGF-β signaling through its interaction with the type III TGF-β receptor.

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