Elevated cyclic AMP Inhibits M. tuberculosis-stimulated T cell IFN-g Secretion through type I Protein Kinase A.

CHUNG; PASQUINELLI V; JURADO JO; WANG; YI; TOWNSEND JC; BARNES PF; GARCIA VE; SAMTEN B

JOURNAL OF INFECTIOUS DISEASES

UNIV CHICAGO PRESS

Año: 2018 vol. 217 p. 1821 - 1831

0022-1899

ENVIADO 2017- ACEPTADO 2018cAMP is critical in immune regulation, and Mycobacterium tuberculosis (Mtb) intoxicates macrophages through cAMP secretion. To examine the role of cAMP in the immune response to Mtb infection, we determined cAMP levels in peripheral blood mononuclear cells (PBMC) from tuberculosis patients and the mechanisms for cAMP suppression of T cell IFN-γ production. PBMC from tuberculosis patients contained significantly higher cAMP levels than latent tuberculosis infected subjects (LTBI), with an inverse correlation with Mtb-stimulated IFN-γ production. The expression of cAMP response element binding protein (CREB), activating transcription factor (ATF)-2 and c-Jun were reduced in tuberculosis patients compared with LTBI. cAMP analogs inhibited Mtb-induced IFN-γ production by PBMC in a PKA type І, but not PKA type II or EPAC (early exchange protein directly activated by cAMP) dependent manner. PKA type I specific cAMP analogs markedly suppressed Mtb-induced IFN-γ promoter binding activities and expression of CREB, ATF-2, and c-Jun as determined by gel shift assay and western blotting, respectively. Consistent with this, miR155, the target miRNA of these transcription factors was reduced by cAMP. Neutralizing both IL-10 and TGF-β1 or supplementation of IL-12 restored cAMP-suppressed IFN-γ production. We conclude that increased cAMP inhibits T-cell IFN-γ production through PKA type I pathway.