title: TRAF6 mediates IL-1β/LPS-induced suppression of TGF-β signaling through its interaction with the type III TGF-β receptor.
abstract: 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 anti-inflammatory signaling in a NF-κB-independent manner. TRAF6, a key molecule in IL-1β signaling, mediates this suppressive effect through interaction with the type III TGF-β receptor (TβRIII), which is TGF-β-dependent and requires type I TGF-β receptor (TβRI) kinase activity. TβRI phosphorylates TβRIII at residue S829, which promotes the TRAF6/TβRIII interaction and consequent sequestration of TβRIII from the TβRII/TβRI complex. Our data indicate that IL-1β enhances the pro-inflammatory response by suppressing TGF-β signaling through TRAF6-mediated sequestration of TβRIII, which may be an important contributor to the early stages of tumor progression.
authors.affiliation: Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Seunghwan
authors.initials: S
authors.lastname: Lim
authors.forename: Eunjin
authors.initials: E
authors.lastname: Bae
authors.forename: Hae-Suk
authors.initials: HS
authors.lastname: Kim
authors.forename: Tae-Aug
authors.initials: TA
authors.lastname: Kim
authors.forename: Kyunghee
authors.initials: K
authors.lastname: Byun
authors.forename: Byungchul
authors.initials: B
authors.lastname: Kim
authors.forename: Suntaek
authors.initials: S
authors.lastname: Hong
authors.forename: Jong Pil
authors.initials: JP
authors.lastname: Im
authors.forename: Chohee
authors.initials: C
authors.lastname: Yun
authors.forename: Bona
authors.initials: B
authors.lastname: Lee
authors.forename: Bonghee
authors.initials: B
authors.lastname: Lee
authors.forename: Seok Hee
authors.initials: SH
authors.lastname: Park
authors.forename: John
authors.initials: J
authors.lastname: Letterio
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D002458:Cell Fractionation; D053938:DNA Fragmentation; D055785:Gene Knockdown Techniques; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides; D051379:Mice; D008856:Microscopy, Fluorescence; D016297:Mutagenesis, Site-Directed; D011509:Proteoglycans / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D011509:Proteoglycans; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D048029:TNF Receptor-Associated Factor 6; D016212:Transforming Growth Factor beta; C071736:betaglycan