Transforming Growth Factor-β Differentially Inhibits MyD88-dependent, but Not TRAM- and TRIF-dependent, Lipopolysaccharide-induced TLR4 Signaling

• Published in: The Journal of biological chemistry 2005-02, Vol.280 (7), p.5491-5495
• Main Authors: Naiki, Yoshikazu, Michelsen, Kathrin S., Zhang, Wenxuang, Chen, Shuang, Doherty, Terence M., Arditi, Moshe
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport - biosynthesis; Adaptor Proteins, Vesicular Transport - metabolism; Antigens, Differentiation - genetics; Antigens, Differentiation - metabolism; Cell Line; Chemokine CCL5 - metabolism; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Humans; Interferon-gamma - metabolism; Ligands; Lipopolysaccharides - pharmacology; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - metabolism; Myeloid Differentiation Factor 88; NF-kappa B - metabolism; Proteasome Endopeptidase Complex - metabolism; Receptors, Cell Surface - metabolism; Receptors, Immunologic - antagonists & inhibitors; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptors; Transforming Growth Factor beta - pharmacology; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha - metabolism; Ubiquitin - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C400503200

Transforming growth factor-β1 (TGF-β1) is a multifunctional, potent anti-inflammatory cytokine produced by many cell types that regulates cell proliferation, apoptosis, and immune responses. Toll-like receptors (TLRs) recognize various pathogen-associated molecular patterns and are therefore a pivotal component of the innate immune system. In this study we show that TGF-β1 blocks the NF-κB activation and cytokine release that is stimulated by ligands for TLRs 2, 4, and 5. We further show that TGF-β1 can specifically interfere with TLR2, -4, or -5 ligand-induced responses involving the adaptor molecule MyD88 (myeloid differentiation factor 88) but not the TRAM/TRIF signaling pathway by decreasing MyD88 protein levels in a dose- and time-dependent manner without altering its mRNA expression. The proteasome inhibitor epoxomicin abolished the MyD88 degradation induced by TGF-β1. Furthermore, TGF-β1 resulted in ubiquitination of MyD88 protein, suggesting that TGF-β1 facilitates ubiquitination and proteasomal degradation of MyD88 and thereby attenuates MyD88-dependent signaling by decreasing cellular levels of MyD88 protein. These findings importantly contribute to our understanding of molecular mechanisms mediating anti-inflammatory modulation of immune responses by TGF-β1.