IFN-γ Production during Active Tuberculosis Is Regulated by Mechanisms That Involve IL-17, SLAM, and CREB

Abstract

Interferon-γ (IFN–γ) is crucial for protection against Mycobacterium tuberculosis, and the transcription factor cAMP response element binding protein (CREB) increases IFN-γ transcription. We determined whether the transmembrane receptor signaling lymphocyte activation molecule (SLAM) and interleukin-17 (IL-17) affect CREB phosphorylation and IFN-γ production in persons with tuberculosis. When T cells from patients with tuberculosis were activated with M. tuberculosis, 80% of SLAM+ T cells expressed phosphorylated CREB, and SLAM activation increased CREB phosphorylation and IFN-γ production. In contrast, IL-17 down-regulated SLAM expression, CREB phosphorylation, and IFN-γ production. Therefore, IL-17 and SLAM have opposing effects on IFN-γ production through CREB activation in persons with tuberculosis.

The IL-17A rs2275913 single nucleotide polymorphism is associated with protection to tuberculosis but related to higher disease severity in Argentina

“…These findings are in line with our previous results demonstrating that Mtb -Ag stimulation of PBMC from TB produced lower IFN-γ levels but higher IL-17A amounts in comparison to HD2239. Moreover, we have also shown that high amounts of recombinant IL-17A in the cell culture inhibited the production of IFN-γ against the pathogen by PBMC23, according to our present data observed in AA TB, where we detected the lowest levels of IFN-γ in the presence of the highest levels of IL-17A (Fig. 4).…”

“…To deeply investigate the hypothesis relating to the AA genotype of the rs2275913 SNP with protection against tuberculosis disease, we next analyzed plasma levels of IFN-γ and IL-17A, two crucial cytokines that participate in the immune response against Mtb 7222332. Then, we determined by ELISA the levels of these two cytokines among individuals carrying the different genotypes of the rs2275913 SNP (Fig.…”

“…Previously, we demonstrated that peripheral blood mononuclear cells (PBMC) from TB stimulated with a lysate of Mtb (Mtb -Ag) secreted lower levels of IFN-γ and higher amounts of IL-17A as compared to healthy donors (HD)22. Furthermore, we showed that addition of recombinant IL-17A to PBMC inhibited IFN-γ production against Mtb- Ag23. We also demonstrated that CD4 + IFN-γ + IL-17A + lymphocytes are the main source of IL-17A produced by PBMC from TB in direct correlation with disease severity22.…”

CgIL17-5, an ancient inflammatory cytokine in Crassostrea gigas exhibiting the heterogeneity functions compared with vertebrate interleukin17 molecules

“…Most of IL-17 downstream genes harbor NF-kB and C/EBP binding sites, both of them are necessary for IL-17-mediated promoter activity (Ruddy et al, 2004;Berger et al, 2006). For instance, CREB phosphorylation induced by IL17 could regulate IFN-g production in persons with tuberculosis (Pasquinelli et al, 2009). There were several putative transcription factor-binding sites located in 5 0 flanking region of CgIL17 genes, including the sites for C/EBP, AP-1, STAT, NF-kB, GATA and Oct-1, which were either directly or indirectly functionally related to immune responses in vertebrates (Cristina et al, 2009;Skjesol et al, 2010;Tripathi and Aggarwal, 2006).…”

CREB Is a Positive Transcriptional Regulator of Gamma Interferon in Latent but Not Active Tuberculosis Infections

“…Humans defective in genes for IFN-␥ or the IFN-␥ receptor are prone to serious mycobacterial infections, including M. tuberculosis. The regulation of IFN-␥ transcription is complex, involving multiple enhancer and repressor elements in response to mycobacterial Ags (12,17). Further work should continue to focus on the mechanism for decreased IFN-␥ production in TB patients, which will enrich our knowledge of protective immunity against M. tuberculosis and contribute to finding new strategies for the control and treatment of TB.…”