Abstract
Lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway is demonstrated to be involved in the hepatic fibrosis. MicroRNA (miR)-146a-5p is a key regulator of the innate immune response. The functional significance of miR-146a-5p during the LPS/TLR4 mediated hepatic fibrosis process remains unclear. In this study, we found that TLR4 and α-smooth muscle actin (α-SMA) were up-regulated and miR-146a-5p was down-regulated in human hepatic stellate cell (HSC) line LX2 after LPS stimulation. Overexpression of miR-146a-5p inhibited LPS induced pro-inflammatory cytokines secretion through down-regulating the expression levels of TLR-4, IL-1 receptor-associated kinase 1 (IRAK1), TNF receptor associated factor-6 (TRAF6) and phosphorylation of nuclear factor-kappa B (NF-κB). Knockdown of IRAK1 and TRAF6 also suppressed pro-inflammatory cytokine production by inhibiting NF-κB phosphorylation. In addition, miR-146a-5p mimic blocked LPS induced TRAF6 dependent c-Jun N-terminal kinase (JNK) and Smad2 activation as well as α-SMA production. Taken together, these results suggest that miR-146a-5p suppresses pro-inflammatory cytokine secretion and cell activation of HSC through inhibition of TLR4/NF-κB and TLR4/TRAF6/JNK pathway.
Highlights
Hepatic fibrosis occurs in response to the chronic liver injury and inflammation induced by viral hepatitis, toxins, autoimmune disease, metabolic disorder and ionizing radiation [1,2]
C2.e1l.lsESxtpimresusliaotnedofwTiothll-LLiipkoepRoleycseapctcohra4ri(dTeL(RLP4)S,)α-Smooth Muscle Actin (α-SMA) and miR-146a-5p in LX2 Cells Stimulated with Lipopolysaccharide (LPS)
Western blot revealed that p-Jun N-terminal kinase (JNK) and p-Smad2 expression were down-regulated in response to TNF Receptor Associated Factor-6 (TRAF6) but not IL-1 Receptor-Associated Kinase 1 (IRAK1) siRNA transfection (Figure 6B)
Summary
Hepatic fibrosis occurs in response to the chronic liver injury and inflammation induced by viral hepatitis, toxins, autoimmune disease, metabolic disorder and ionizing radiation [1,2]. With the prolonged stimulation of injurious agents or pro-inflammatory cytokines, HSCs are activated and transformed into myofibroblast-like cells that produce excessive extracellular matrix components (ECM), such as α-smooth muscle actin (α-SMA), leading eventually to liver fibrosis [3]. Inhibition of HSC activation may be an efficient way to reverse fibrosis. It is well known that by recognizing LPS, TLR4 mediates signal transduction through the MyD88 or Toll/IL-1 receptor kInnt.oJw. Mnolt.hSacit. 2b0y16r,e1c7o, 1g0n76izing LPS, TLR4 mediates signal transduction through the MyD88 or Toll2/IoLf -113 receptor domain-containing adaptor inducing IFN-β (TRIF)-dependent pathway and induces sdeocmreatiionn-coonftapirnoi-nignflaadmapmtaotroirnydcuyctionkginIFeNs -nβec(eTsRsaIFry)-dfeopr etnhdeendtevpealtohpwmaeynat nodf ienfdfeuccteivseseimcremtiuonnitoyf. THheowpreovceers,sthoef fhuenpcattiiocnfiabl rsoisginsiftihcraonucgehorfegmuilRat-i1n4g6at-h5eppdroulriifnergattihoen aLnPdS/aTcLtiRv4atmionedoiaf tHedSChsep[1a2t,i1c3]f.ibHrooswisevperor,ctehses rfuemncatiinosnaulnscilgeanri.fiIcnanthcee pofremseinRt-1st4u6da-y5,pwdeuforiunngdththeatLmPSiR/T-1L4R6a4-5mpeodviaetreedxphreespsaiotinc sfiubpropsriesssperdocLePsSs irnedmuaciends upnroc-leinafrl.amInmathtoeryprceysetonktinsteusdsye,cwreetiofnouannddthHaStCmaiRct-i1v4a6taio-5npthorvoeuregxhprineshsiibointiosnupopfreTsLsRed sLiPgSnainlidngucpeadthpwroa-yin. Flammatory cytokines secretion and HSC activation through inhibition of TLR4
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