Depressed CCL5 Expression in Human Pulmonary Tuberculosis

ABSTRACT

CCL5/regulated on activation, normal T expressed and secreted production (RANTES) is a principal CC chemokine, and can activate macrophages and Th1 lymphocytes, however, little is known about the CCL5 profiles associated with active tuberculosis (TB). In this study, we investigated the production of CCL5 by the peripheral blood mononuclear cells (PBMCs) of patients with active pulmonary TB after stimulation with Triton X-100 soluble proteins (TSP) or the 30-kDa antigen. The profiles of cytokines/chemokines [CXCL8/interleukin (IL)-8, IL-12 p40, and interferon (IFN)-gamma] were also examined by PBMCs from TB patients, and compared with those obtained from healthy tuberculin reactors (HTR). Concordant with earlier studies, IFN-gamma production was significantly depressed in the PBMCs from TB patients compared with those from HTR. In addition, the CCL5, but not CXCL8, levels in the PBMCs from TB patients were significantly depressed after stimulation for 18 hr compared to those in the PBMCs from HTRs. The CCL5 release was not significantly correlated with the release of IFN-gamma in the cells from TB patients and HTRs. Further, inhibitor studies show that the 30-kDa- or TSP-induced CCL5 mRNA expression is sensitive to inhibitors of mitogen-activated protein kinase kinase (MEK) 1/2 and Janus kinase (JAK) 2, but not p38, pathway activation, suggesting a MEK1/2- or JAK2-based mechanism is responsible for modulating of the CCL5 expression in human PBMCs. Collectively, these data suggest that TB patients show depressed production of CCL5 secretion, which can be modulated by MEK- and JAK2-based transcriptional regulatory mechanisms, in response to the mycobacterial antigens.