Andrographolide inhibits STAT1 expression and desensitizes interferon γ-induced priming in macrophage cells

Background The herbal medicine Andrographis paniculata has broad anti-inflammatory effects. In the present study, we aimed to clarify whether andrographolide (And), neoandrographolide (Neo), and deoxyandrographolide (Deo), three of the most abundant bioactive diterpene lactone compounds in A. paniculata , can modulate the pro-inflammatory priming effects of interferon (IFN)-γ in macrophage cells. Methods The human monocytic cell line THP-1 was pre-activated with lipopolysaccharide (LPS) or phorbol 12-myristate 13-acetate (PMA). Murine and human primary macrophage cells were pre-activated with LPS. Results In THP-1 cells, we showed that both LPS and PMA stimulated the expression of signal transducer and activator of transcription 1 (STAT1), the pivotal signaling module in type I and II IFNs; these responses were blunted by And at non-cytotoxic concentrations but not by Neo or Deo. In parallel, And significantly inhibited the priming effects of IFN-γ, including upregulation of the pro-inflammatory chemokine monocyte chemoattractant protein-1 and the NADPH oxidase subunit gp91phox. Mechanistically, we showed that the inhibitory effects of And on STAT1 expression in both LPS- and PMA-activated macrophages were, at least partly, attributable to the reduction in IFN-β expression, but not related to changes in IFN-β-induced activation of the transcription factor complex IFN-stimulated gene factor 3 or the stability of STAT1 mRNA. We confirmed the inhibitory effects of And on STAT1 expression and IFN-γ-induced priming in murine or human primary macrophages. Conclusion Our results suggest that And may desensitize macrophage cells to IFN-γ-induced priming by inhibiting STAT1 expression. This effect of And may partly explain the multiple anti-inflammatory actions of this compound.