Diagrammatic representation of intracellular pathways that lead to the production of IL-12p40 and the mechanisms of azithromycin (AZM) to inhibit the expression of IL-12p40 upon the stimulation of LPS/IFNG

Diagrammatic representation of intracellular pathways that lead to the production of IL-12p40 and the mechanisms of azithromycin (AZM) to inhibit the expression of IL-12p40 upon the stimulation of LPS/IFN-γ. (A) Inflammatory stimulation leads to the activation of various signal transduction cascades in cells. Binding of LPS and toll-like receptor (TLR)-4 activates NF-κB. Soon after occurring LPS/TLR-4 signaling, IKB is degraded in this process. Subsequently, NF-κB translocates into the nucleus, and binds to its binding motif in promoter region of IL-12p40. Moreover, LPS/TLR-4 signaling results in the activation of MAPK pathway, which leads to the phosphorylation of activator protein (AP)-1, such as JunB. Phosphorylated AP-1 binds to its binding motif in the promoter. Binding of IFN-γ and its receptor activates JAK-STAT pathways, and other pathways, such as PI3K and Pyk2. Activated STAT1 phosphorylates ICSBP. In this cellular activation process, calcium influx is induced, and elevated intracellular concentration of calcium activates calcineurin. Then, NFAT is dephosphorylated by activated calcineurin, and subsequently translocates into the nucleus. NFAT heterodimerizes with ICSBP, and this heterodimer binds to the binding motif in promoter. Activated PI3K and Pyk2 also activate the MAPK pathway. (B) In the presence of AZM, the phosphorylation of ICSBP and JunB is inhibited. This inhibition results in the reduced binding capacity of ICSBP/NFAT and JunB to their DNA binding motif in the IL-12p40 promoter, and IL-12p40 gene expression is suppressed. It was also reported that AZM inhibits NF-κB pathway by reducing the degradation of IKB (reference 23). Abbreviations: ICSBP, interferon consensus sequence binding protein; IKB, inhibitor of κB; JAK, Janus kinase; MAPK, mitogen activated protein kinase; MyD88, myeloid differentiation primary response gene 88; NFAT, nuclear factor of activated T-cells; NF-κB, nuclear factor-κB; PI3K, phosphatidylinositol 3-kinase, Pyk2, calcium-dependent tyrosine kinase; STAT1, signal transducer and activator of transcription 1; TAK1, transforming growth factor-beta-activated kinase 1; TRA6, TNF receptor-associated factor 6.

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Azithromycin suppresses interleukin-12p40 expression in lipopolysaccharide and interferon-γ stimulated macrophages. (2009) Keiko Yamauchi, et al. Int J Biol Sci. 2009;5(7):667-678. Figure: F6. All organisms Oryctolagus cuniculus Homo sapiens Mus musculus Drosophila melanogaster

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