Opposing cytokine-specific effects of all trans-retinoic acid on the activation and expression of signal transducer and activator of transcription (STAT)-1 in THP-1 cells

The regulation of signal transducer and activator of transcription-1 (STAT-1) by cytokines and all-trans -retinoic acid (RA) was investigated in THP-1 monocytic cells cultured with RA and stimulated with lipopolysaccharide (LPS), tumour necrosis factor-alpha (TNF-alpha), interferon-beta (IFN-beta), and IFN-gamma, individually or in combinations. While RA (10(-8) m) alone did not alter STAT-1 activation or expression in THP-1 cells, RA enhanced or prolonged STAT-1 activation (tyrosine 701 phosphorylation) and gene expression (mRNA and protein) induced by either IFN-beta or IFN-gamma. However, in contrast, RA reduced STAT-1 activation and gene expression induced by LPS and/or TNF-alpha by about 50-70%, and lowered in vitro DNA binding activity to both a STAT-1 consensus element and a nuclear factor kappa B (NFkappaB) binding element. These results imply that RA can significantly rebalance STAT-1-dependent responses, and that one of the mechanisms may be through the inhibition of the NFkappaB pathway.