We investigated the association of SOCS with disease progression in patients with pulmonary TB. For this purpose, we studied peripheral

blood mononuclear cells (PBMCs) and T cells from patients with pulmonary TB (TB, n = 33) and healthy endemic controls (EC, n = 15). Cases were stratified into those with moderately advanced (Mod-PTB) or far advanced disease (Adv-PTB). Interferon-gamma (IFN-γ), SOCS1 and SOCS3 gene expression was determined by RT-PCR. Statistical analysis was performed using the Mann–Whitney test. Levels of IL6 (P = 0.018) and IL10 (P = 0.013) were found to be elevated in PBMC supernatants from patients with TB as compared with EC. SOCS1 mRNA gene expression in T cells from patients with TB was increased as compared with that of EC (P = 0.02). In addition, levels of SOCS1 mRNA transcripts were found to be Ridaforolimus elevated in PBMCs of Adv-PTB as compared with Mod-PTB Nutlin-3a (P = 0.008) cases. Our data show that raised SOCS1 levels are associated with increased disease severity in TB. As SOCS1 regulates IFN-γ-driven immunity and SOCS1 can be further upregulated by IL6 levels, the increase in SOCS1 in severe disease indicates a mechanism by which mycobacteria impede disease control in TB. One-third of the world’s population has been estimated to be infected with Mycobacterium tuberculosis, which causes 1.8 million deaths annually [1, 2]. The interplay between host T cell and macrophages by appropriate

activation of cytokines such as IFN-γ and TNFα results in restriction of mycobacterial infection by appropriate granuloma formation [3]. CD4+ T cells play a central role in containment of M. tuberculosis infection by secreting interferon-gamma (IFN-γ) [4]. The enhanced susceptibility to mycobacterial infection of IFN-γ knockout mice [5, 6], and of patients with genetic defects in IL12/IFN-γ pathway [7] and the lowered antigen-stimulated T-cells IFN-γ responses in patients with active tuberculosis (TB) [8–11] all provide strong evidence that IFN-γ plays a significant role in defence against M. tuberculosis. Interferon-gamma activates Sulfite dehydrogenase transcriptional expression of IFN-γ response

genes mediated by the signal transducer and activator of transcription (STAT)-1 molecule [12]. An essential component of cytokine regulation is the timely termination of signals. Suppressor of cytokine signalling (SOCS) are a family of molecules that act as negative regulators of cytokine signalling by inhibiting Janus-activated kinase (JAK)/STAT activation [13] and thus affect immune responses to infection in the host. SOCS1 inhibits STAT1 activation and thereby the expression of IFN-γ-mediated genes [14, 15]. M. tuberculosis-induced IL6 has been shown to upregulate SOCS1 expression in activated CD4+ T cells, thereby interfering with STAT1 phosphorylation induced by IFN-γ [16]. SOCS1−/− mice die within three weeks after birth because of uncontrolled IFN-γ signalling [17].