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Azithromycin Polarizes Macrophages to an M2 Phenotype via Inhibition of the STAT1 and NF-?B Signaling Pathways.

ABSTRACT: Azithromycin is effective at controlling exaggerated inflammation and slowing the long-term decline of lung function in patients with cystic fibrosis. We previously demonstrated that the drug shifts macrophage polarization toward an alternative, anti-inflammatory phenotype. In this study we investigated the immunomodulatory mechanism of azithromycin through its alteration of signaling via the NF-?B and STAT1 pathways. J774 murine macrophages were plated, polarized (with IFN-?, IL-4/-13, or with azithromycin plus IFN-?) and stimulated with LPS. The effect of azithromycin on NF-?B and STAT1 signaling mediators was assessed by Western blot, homogeneous time-resolved fluorescence assay, nuclear translocation assay, and immunofluorescence. The drug's effect on gene and protein expression of arginase was evaluated as a marker of alternative macrophage activation. Azithromycin blocked NF-?B activation by decreasing p65 nuclear translocation, although blunting the degradation of I?B? was due, at least in part, to a decrease in IKK? kinase activity. A direct correlation was observed between increasing azithromycin concentrations and increased IKK? protein expression. Moreover, incubation with the IKK? inhibitor IKK16 decreased arginase expression and activity in azithromycin-treated cells but not in cells treated with IL-4 and IL-13. Importantly, azithromycin treatment also decreased STAT1 phosphorylation in a concentration-dependent manner, an effect that was reversed with IKK16 treatment. We conclude that azithromycin anti-inflammatory mechanisms involve inhibition of the STAT1 and NF-?B signaling pathways through the drug's effect on p65 nuclear translocation and IKK?.

SUBMITTER: Haydar D

PROVIDER: S-EPMC6684391 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Azithromycin Polarizes Macrophages to an M2 Phenotype via Inhibition of the STAT1 and NF-κB Signaling Pathways.

Haydar Dalia D Cory Theodore J TJ Birket Susan E SE Murphy Brian S BS Pennypacker Keith R KR Sinai Anthony P AP Feola David J DJ

Journal of immunology (Baltimore, Md. : 1950) 20190701 4

Azithromycin is effective at controlling exaggerated inflammation and slowing the long-term decline of lung function in patients with cystic fibrosis. We previously demonstrated that the drug shifts macrophage polarization toward an alternative, anti-inflammatory phenotype. In this study we investigated the immunomodulatory mechanism of azithromycin through its alteration of signaling via the NF-κB and STAT1 pathways. J774 murine macrophages were plated, polarized (with IFN-γ, IL-4/-13, or with ...[more]

PMID: 31263039

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Project description:Background:Tumor-associated macrophage (TAM) is emerging as one of the important complications in cancer promotion. Interleukin-17 (IL-17), a potent pro-inflammatory cytokine, plays an active role in promoting M2 macrophage differentiation (TAMs are M2-like phenotypes). In this study, we aimed to evaluate that IL-17 stimulates key phenotypic and functional signatures of M2 macrophages associated with cancer progression in non-small-cell lung cancer (NSCLC) patients. Patients and methods:The markers and cytokines of M2 macrophages were detected in THP-1-derived macrophages and mouse peritoneal macrophages treated with IL-17. The activation of nuclear factor kappa B (NF-?B) and nuclear localization of p65 in IL-17-treated cells were investigated. The BAY11-7082 inhibitor and the siRNA of p65 were used to block the NF-?B activation. A total of 85 patients who underwent surgery for histologically verified NSCLC were enrolled in this study. The expression of IL-17 and M2 macrophage markers were assessed by immunostaining. Survivals were estimated using the Kaplan-Meier method. Results:The CD163 and CD206 cell surface markers and transforming growth factor beta (TGF-?), vascular endothelial growth factor (VEGF) and IL-10 of M2 macrophages were significantly increased in IL-17-treated THP-1-derived macrophages in a dose-dependent manner. IL-17 increased the mRNA levels of Arginase I and Fizz1, the phosphorylation of IkB? and nuclear localization of p65 (a subunit of NF-?B). The BAY11-7082 abrogated IL-17-induced CD206 and CD163 expression, TGF-?, VEGF, IL-10, Arginase I and Fizz1 expression and p65 nuclear translocation. Further experiments showed that IL-17 induced the expression of CD206, CD163, Arginase I, Fizz1 and Ym1 in mouse peritoneal macrophages that were inhibited by siRNA of p65. The immunostaining experiments on human NSCLC tissues indicated that high IL-17 expression was significantly correlated with CD163 and c-Maf. The intratumoral IL-17+ CD163+ c-Maf+ cells were associated with NSCLC progression. Conclusion:IL-17 stimulated macrophages to M2-like phenotypes via NF-?B activation. IL-17 may be a potential therapeutic target for NSCLC.

Dataset Information

Azithromycin Polarizes Macrophages to an M2 Phenotype via Inhibition of the STAT1 and NF-?B Signaling Pathways.

Publications

Azithromycin Polarizes Macrophages to an M2 Phenotype via Inhibition of the STAT1 and NF-κB Signaling Pathways.

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