Expression of M. tuberculosis-induced suppressor of cytokine signaling (SOCS) 1, SOCS3, FoxP3 and secretion of IL-6 associates with differing clinical severity of tuberculosis

Abstract

BackgroundAppropriate immune activation of T cells and macrophages is central for the control of Mycobacterium tuberculosis infections. IFN-γ stimulated responses are lowered in tuberculosis (TB), while expression of Suppressor of Cytokine Signaling (SOCS) molecules – 1 and 3 and CD4+CD25+FoxP3+T regulatory cells is increased. Here we investigated the association of these molecules in regard to clinical severity of TB.MethodsPeripheral blood mononuclear cells (PBMCs) were isolated from patients with pulmonary TB (PTB, n = 33), extra-pulmonary TB (ETB, n = 33) and healthy endemic controls (EC, n = 15). Cases were classified as moderately advanced or far advanced PTB, and less severe or severe disseminated ETB. M. tuberculosis -stimulated IFN-γ, SOCS1, SOCS3 and FoxP3 gene expression and secretion of Th1 and Th2 cytokines was measured. Statistical analysis was performed using Mann–Whitney U, Wilcoxon Rank and Kruskal Wallis non-parametric tests.ResultsIn un-stimulated PBMCs, IL-6 (p = 0.018) and IL-10 (p = 0.013) secretion levels were increased in PTB while IL-10 was also increased in ETB (p = 0.003), all in comparison with EC. M. tuberculosis-stimulated IL-6 (p = 0.003) was lowered in ETB as compared with EC. SOCS1 mRNA expression in M. tuberculosis stimulated PBMCs levels in moderately advanced PTB (p = 0.022), far advanced (p = 0.014) PTB, and severe ETB (p = 0.009) were raised as compared with EC. On the other hand, SOCS1 mRNA titers were reduced in less severe ETB, in comparison with severe ETB (p = 0.027) and far advanced PTB (p = 0.016). SOCS3 mRNA accumulation was reduced in far advanced PTB (p = 0.007) and FoxP3 mRNA expression was increased in less severe ETB as compared with EC (p = 0.017).ConclusionsThe lowered SOCS1 mRNA levels in patients with less severe extra-pulmonary TB as compared to those with more severe ETB and PTB may lead to elevated IFN-γ pathway gene expression in the latter group. As localized ETB has shown to be associated with more effective Th1 immunity and adaptive responses, this suggests a role for SOCS1 in determining disease outcome in extra-pulmonary TB.

Fusion protein of tapasin and hepatitis B core antigen 18-27 enhances T helper cell type 1/2 cytokine ratio and antiviral immunity by inhibiting suppressors of cytokine signaling family members 1/3 in hepatitis B virus transgenic mice

“…Signal downregulation through SOCS members has been demonstrated to be important in the balance of cytokines that determines the onset of Th1 and Th2-mediated immune responses. In particular, for cytokine-induced SOCS1 and SOCS3, a role in the regulation of T cell differentiation has been discussed (12)(13)(14).…”

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

“…Moreover, Ifnar1 2/2 mouse macrophages express lower levels of Socs1 during mycobacterial infection, and IFN-g-activated Socs1 2/2 macrophages have lower intracellular bacteria as a result of the increased IFN-g signaling (91). These experimental findings, together with the clinical observation that increased SOCS protein expression correlates with increased disease severity (92,93), hint that a detrimental role for type I IFNs in M. tuberculosis infection is to antagonize host-protective functions of IFN-g. TB is not the only mycobacterial disease associated with type I IFN induction. Self-healing tuberculoid leprosy is traditionally associated with the development of a Th1 response, whereas disseminated lepromatous leprosy is characterized by a Th2 response.…”

The EFFECT OF ALPHA-MANGOSTIN IN BALANCING THE RATIO OF CYTOKINES PRO-AND ANTI-INFLAMMATION-GAMMA (IFN-γ/IL-10) AND SEVERITY OF THE DISEASE IN MICE INFECTED WITH MYCOBACTERIUM TUBERCULOSIS MULTIDRUG-RESISTANT

“…NK cells were produced IFN-γ as a triggers the activation of macrophages and increasing destruction of intracellular bacteria such as MTB [4]. Cytokine IFN-γ stimulated and activated macrophages to produce a substance that eliminates bacteria, including oxidase enzyme in phagocytes, such as reactive oxygen intermediates (ROI), enzyme inducible nitric oxide synthase, and enzyme lysozyme [4][5][6][7][8].…”

“…Tregs are a subpopulation of CD4 + T-cells, expressing and secreting IL-10 and TGF-β, cytokine IL-10 as a barrier and decreasing Th 1 cell response in patients with TB infection. Tregs cells are a major source of cytokines IL-10, which serves to suppressed the function of APC and macrophages activation [4,5]. Infections TB were performed in mice showed that macrophages with excessive production of IL-10 causes of decreased production of ROI and RNI and reduced the function macrophages [11].…”

“…The activity of T-cells (lymphocytes T) was sensitized, and macrophage activation is key to host immunity against intracellular infections such as pulmonary TB [4]. Protection against M. TB infection is a function of the interaction between host T-cells and macrophages and that is coordinated by cytokines [5]. Macrophages represent the first line of defense against invading bacterial pathogens such as Mycobacterial TB (MTB) [6].…”