Schematic representation of NF-κB and STAT signaling pathway in regulation of cytokine gene expression in macrophages. TLR/IL-1R pathway, IL-1R, and all TLRs (except TLR3) signal through the adaptor protein MyD88, leading to NF-κB activation and transcription of proinflammatory cytokine genes. It also triggers activation of MAPKs (eg, JNK, p38) and its downstream transcription factor, AP-1, which coregulates proinflammatory cytokine expression. The TRIF or MyD88-independent signaling pathway triggered by TLR4 or TLR3 signals via the adaptor protein TRIF, which induces a phosphorylation cascade involving activation of IKKi, TBK1, and downstream transcription factor IRF3, leading to IFN-β transcription. IFN-β in turn binds to its cognate receptor (IFNAR1/2) and induces STAT1-mediated expression of IFN-inducible chemokine genes. IFNAR1/2 also serves as the receptor for IFN-α and IFN-γ. The requirement for IRFs is also shown. STAT3 and STAT6 activation induced by IL-10, IL-4, and IL-13 regulates the expression of several M2 genes and also inhibits STAT1 induction. p50 NF-κB homodimers also negatively regulated TLR/IL-1R signaling. Distinct transcription factor specific binding consensus sequences on gene promoters are indicated with different colors. “P” indicates phosphorylation; red T-bars indicate negative regulation.