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* Pulmonary Center, School of Medicine, Boston University, Boston, MA 02118;
Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, MD 21205; and
Department of Microbiology and Genetics, Darmstadt University of Technology, Darmstadt, Germany
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-
production and phosphorylation of
the transcription factor STAT1. TLR4, but not TLR2, agonists can induce
IFN- 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-. 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-. Although exogenous
IFN- and IFN-
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.
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