The IκB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR-IL-1R by controlling degradation of regnase-1.
ABSTRACT Toll-like receptor (TLR) signaling activates the inhibitor of transcription factor NF-κB (IκB) kinase (IKK) complex, which governs NF-κB-mediated transcription during inflammation. The RNase regnase-1 serves a critical role in preventing autoimmunity by controlling the stability of mRNAs that encode cytokines. Here we show that the IKK complex controlled the stability of mRNA for interleukin 6 (IL-6) by phosphorylating regnase-1 in response to stimulation via the IL-1 receptor (IL-1R) or TLR. Phosphorylated regnase-1 underwent ubiquitination and degradation. Regnase-1 was reexpressed in IL-1R- or TLR-activated cells after a period of lower expression. Regnase-1 mRNA was negatively regulated by regnase-1 itself via a stem-loop region present in the regnase-1 3' untranslated region. Our data demonstrate that the IKK complex phosphorylates not only IκBα, thereby activating transcription, but also regnase-1, thereby releasing a 'brake' on IL-6 mRNA expression.
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ABSTRACT: Nickel (Ni) ions easily elute from many alloys and elicit inflammation and allergies. Previous studies have shown that infections due to the implantation of medical devices cause inflammation and enhance the elution of Ni ions (Ni2+). However, cross-talk between infection- and Ni2+-induced signaling pathways has not yet been elucidated in detail. In the present study, we investigated the effects of Ni2+ on the lipopolysaccharide (LPS)-induced production of cytokines in a LPS-induced air pouch-type inflammation model in BALB/c mice and the murine macrophage cell line RAW264. We demonstrated that Ni2+ inhibited the LPS-induced production of interleukin (IL)-6, but not that of tumor necrosis factor (TNF)-α both in vivo and in vitro. This inhibitory effect was also observed with cobalt ion (Co2+), but not with chloride ion (Cl-), zinc ion (Zn2+), or palladium ion (Pd2+), and was highly selective to the production of IL-6. Ni2+ did not inhibit the activation of ERK1/2, p38 MAPK, or JNK. Although Ni2+ decreased IL-6 mRNA levels, it failed to inhibit the LPS-induced activation of the IL-6 promoter. An experiment using actinomycin D, a transcription inhibitor, revealed that Ni2+ decreased the stability of IL-6 mRNA. Moreover, Ni2+ inhibited the LPS-induced expression of Arid5a, but not regnase-1. These results demonstrated that Ni2+ may have selectively inhibited the LPS-induced production of IL-6 by decreasing the Arid5a-dependent stabilization of IL-6 mRNA.PLoS ONE 01/2015; 10(3):e0119428. DOI:10.1371/journal.pone.0119428 · 3.53 Impact Factor
Dataset: ICS 2014 1 e244 TFL Rev
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ABSTRACT: Post-transcriptional modulation of inflammatory molecules is recently recognized for fine-tuning of inflammatory initiation and maintenance. In these molecules, some families with three cytosines and a histidine type of zinc finger domain are gaining attention. Among them, MCP-1 induced protein (MCPIP), also known as regulatory RNase 1 (Regnase-1), encoded by the Zc3h12a gene is recently recognized as a novel player for the inflammatory response. Meanwhile, the Transformed follicular lymphoma (TFL) gene is identified as a putative tumor suppressor gene for lung carcinoma, as well as malignant lymphoma. TFL is a member of the Zc3h12 gene family; hence, it is named as Zc3h12d. It has Nedd4-binding protein 1 and bacterial YacP-like protein domains, which resemble the N-terminus of PilT protein, acts as a ribonuclease, and degrades several cytokines similar to Regnase-1. TFL encodes mainly the 58Kda protein, p58TFL, which is expressed dominantly in lymphoid organs and is upregulated in activated T and B cells according to the inflammatory response. In contrast, MCPIP/Regnase-1 is expressed mainly in macrophages and for a short term in activated lymphocytes. TFL inhibits cell growth via upstream inhibition of the Rb signaling pathway like a tumor suppressor. Moreover, in contrast to other Zc3h12 family members, expression of TFL is increased slowly in activated lymphocytes, and inflammatory resolution is modulated, which is vital for tissue regeneration. Inflammatory dysregulation by TFL deficiencies brings about prolonged inflammation and may give rise to tumor susceptibility in lymphomagenesis. Therefore, TFL can be considered a novel regulatory marker of inflammation, as well as an indicator for tumor progression.