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

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.

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.

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.

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.