title: Thymosin beta4 inhibits TNF-alpha-induced NF-kappaB activation, IL-8 expression, and the sensitizing effects by its partners PINCH-1 and ILK.
abstract: The mechanisms by which thymosin β 4 (Tβ(4)) regulates the inflammatory response to injury are poorly understood. Previously, we demonstrated that ectopic Tβ(4) treatment inhibits injury-induced proinflammatory cytokine and chemokine production. We have also shown that Tβ(4) suppresses TNF-α-mediated NF-κB activation. Herein, we present novel evidence that Tβ(4) directly targets the NF-κB RelA/p65 subunit. We find that enforced expression of Tβ(4) interferes with TNF-α-mediated NF-κB activation, as well as downstream IL-8 gene transcription. These activities are independent of the G-actin-binding properties of Tβ(4). Tβ(4) blocks RelA/p65 nuclear translocation and targeting to the cognate κB site in the proximal region of the IL-8 gene promoter. Tβ(4) also inhibits the sensitizing effects of its intracellular binding partners, PINCH-1 and ILK, on NF-κB activity after TNF-α stimulation. The identification of a functional regulatory role by Tβ(4) and the focal adhesion proteins PINCH-1 and ILK on NF-κB activity in this study opens a new window for scientific exploration of how Tβ(4) modulates inflammation. In addition, the results of this study serve as a foundation for developing Tβ(4) as a new anti-inflammatory therapy.
authors.affiliation: Department of Ophthalmology, Kresge Eye Institute, Detroit, Michigan, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Qiu
authors.forename: Michelle Kurpakus
authors.initials: MK
authors.lastname: Wheater
authors.forename: Yue
authors.initials: Y
authors.lastname: Qiu
authors.forename: Gabriel
authors.initials: G
authors.lastname: Sosne
mesh_terms: D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D013947:Thymosin / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000099201:Thymosin beta(4); D000099200:Scaffold Protein ILK
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D000893:Anti-Inflammatory Agents; D004268:DNA-Binding Proteins; D016209:Interleukin-8; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D013947:Thymosin; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000099201:Thymosin beta(4); D000099200:Scaffold Protein ILK; C088088:LIMS1 protein, human