TableEdit

Schilling, D, Thomas, K, Nixdorff, K, Vogel, SN and Fenton, MJ (2002) Toll-like receptor 4 and Toll-IL-1 receptor domain-containing adapter protein (TIRAP)/myeloid differentiation protein 88 adapter-like (Mal) contribute to maximal IL-6 expression in macrophages. J. Immunol. 169:5874-80

Previous studies have shown that engagement of Toll-like receptors (TLR) 2 and 4 can induce macrophages to express a variety of proinflammatory cytokines. We have recently demonstrated that TLR2 agonists poorly induce a subset of TLR4-inducible proinflammatory genes (e.g., inducible protein (IP)-10, inducible NO synthase (iNOS), monocyte chemoattractant protein-5, IL-12p40), due in part to differential activation of IFN-beta production and phosphorylation of the transcription factor STAT1. TLR4, but not TLR2, agonists can induce IFN-beta expression via a mechanism that requires the adapter protein Toll-IL-1R domain-containing adapter protein (TIRAP)/myeloid differentiation protein 88 (MyD88) adapter-like (Mal), but not the adapter protein MyD88. Thus, the failure of TLR2 agonists to induce STAT1-dependent genes results, in part, from their failure to induce the expression of IFN-beta. In this study, we show that IL-6 expression is also preferentially induced by activation of TLR4. TLR4-dependent induction of IL-6 expression did require Toll-IL-1R domain-containing adapter protein (TIRAP)/MyD88 adapter-like (Mal), but unlike iNOS and IP-10, it did not require the expression of IFN-beta. Although exogenous IFN-beta and IFN-gamma could synergize with TLR2 agonists to restore high levels of iNOS expression and NO production, these IFNs could not synergize with TLR2 agonists to induce high levels of IL-6. Similarly, neutralizing anti-IFN Abs could block iNOS gene expression in LPS-stimulated murine macrophages, whereas these Abs had little effect on IL-6 gene expression in these cells. Together, these studies demonstrate that IL-6, like iNOS and IP-10, is differentially expressed in macrophages stimulated via TLR2 vs TLR4, although these differences appear to arise from distinct signaling mechanisms.

PubMed

Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Animals; Antigens, Differentiation/physiology; Bacterial Proteins/pharmacology; Bone Marrow Cells/immunology; Bone Marrow Cells/metabolism; Carrier Proteins/physiology; Cell Line; Cysteine/analogs & derivatives; Cysteine/pharmacology; Drosophila Proteins; Drug Synergism; Interferon Type I/physiology; Interferon Type I/secretion; Interferon-beta/pharmacology; Interferon-gamma/pharmacology; Interleukin-6/biosynthesis; Interleukin-6/genetics; Lipopolysaccharides/pharmacology; Lipoproteins/pharmacology; Macrophages/immunology; Macrophages/metabolism; Macrophages, Peritoneal/immunology; Macrophages, Peritoneal/metabolism; Membrane Glycoproteins/agonists; Membrane Glycoproteins/physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Myeloid Differentiation Factor 88; Nitric Oxide Synthase/biosynthesis; Nitric Oxide Synthase/genetics; Nitric Oxide Synthase Type II; Protein Biosynthesis; Proteins/physiology; Receptors, Cell Surface/agonists; Receptors, Cell Surface/physiology; Receptors, Immunologic/physiology; Receptors, Interleukin-1/physiology; Signal Transduction/drug effects; Signal Transduction/immunology; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptors; Tumor Necrosis Factor-alpha/pharmacology; eIF-2 Kinase/deficiency; eIF-2 Kinase/genetics; eIF-2 Kinase/physiology