Aberrant Toll receptor expression and endotoxin hypersensitivity in mice lacking a functional TGF-beta 1 signaling pathway.
TGF-beta1 plays a central role in maintaining normal immune function and deficiency of this potent immunosuppressive molecule is linked to uncontrolled inflammation, cachexia, and multiorgan failure as seen in the TGF-beta1 null mouse. Infiltration of inflammatory cells into vital organs of the null mouse is accompanied by increased gene expression of inflammatory cytokines, including TNF-alpha and IL-1beta, as well as inducible NO synthase, each regulated by NF-kappaB. Treatment with the proteasome inhibitor MG132 to prevent NF-kappaB activation dramatically reduced NO production and expression of inflammatory cytokines. This inflammatory phenotype with NF-kappaB activation in the TGF-beta1 null mouse, in the absence of any identifiable pathogen, suggested activation of innate immune responses. Because Toll-like receptors (TLR) are essential in the activation of innate immunity, we examined inflamed tissue from TGF-beta1 null and wild-type mice for expression of TLR4, the receptor that interacts with bacterial cell wall LPS to initiate an NF-kappaB-dependent signaling pathway, leading to gene transcription of inflammatory mediators. Increased TLR4 mRNA expression observed in TGF-beta1 null mice as well as in mice lacking the TGF-beta transcription factor Smad3 was associated with LPS hyperresponsiveness leading to increased expression of inflammatory cytokines and NO and endotoxemia. Furthermore, mice lacking both TGF-beta1 and a functional TLR4 were resistant to endotoxin shock. Constitutive and/or environmental activation of TLR4 and downstream elements, in the absence of TGF-beta suppression, may impact on innate and adaptive immunity and contribute to massive uncontrolled inflammation.
McCartney-Francis
Nancy
N
Cellular Immunology Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA. nfrancis@dir.nidcr.nih.gov
Jin
Wenwen
W
Wahl
Sharon M
SM
D000818:Animals; D019446:Endotoxemia / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D007113:Immunity, Innate / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000633:toxicity*; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009102:Multiple Organ Failure / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D016212:Transforming Growth Factor beta / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; C508961:Tgfb1 protein, mouse; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D009569:Nitric Oxide