In vitro Evaluation of Anti-Apoptotic Potential of IL-6 in Primary Culture of Peripheral Blood Mononuclear Cells Derived from Chronic HCV Patients

Abstract

Chronic HCV infection appears to trigger the impairment and exhaustion of immune cells, to potentially assist viral persistence and disease progression. In individuals where HCV infection is not resolved, the virus promotes functional exhaustion of HCV specific T cells, anergy and deletion owing to lack of positive stimulation, upregulation of inhibitory receptors and death markers, and rapid expansion of regulatory T cells (Tregs). Continuous evidence has suggested that the spontaneous apoptosis of peripheral blood mononuclear cells (PBMCs) could be one of the mechanisms responsible for diminished immune response in chronic viral infection (Barathan et al., 2015). Interleukin 6 is a pleiotropic cytokine which plays an essential role in immune responses against infection. It acts both as a pro-inflammatory and anti-inflammatory cytokine. IL-6 is a prominent regulator of transition from non-specific innate immunity to a more specialized and highly specific adaptive immunity against infection. Furthermore, T cell homeostasis and functionality is critically monitored by IL-6 which ensures an efficient and sustained adaptive immunity. The present study investigates protective effect of Interleukin-6 in rescuing PBMCs from apoptosis and exhaustion induced by chronic HCV infection. Resistance to apoptosis by upregulating anti-apoptotic proteins can allow long lasting survival of T cells even in the absence of nutrients and growth factors. T cell death due to exhaustion or deprivation of cytokine and growth signal is strictly controlled by Bcl-2 family members such BIM and MCL-1. In this study, we identified the pro-inflammatory cytokine IL-6 as a potential homeostatic cytokine that expands T cell space by inducing expression of anti-apoptotic genes, such as Mcl-1, Bcl-2 (3 folds and 2 folds’ change in gene expression respectively) and by downregulating expression of T cell inhibitory receptor TIM-3. Similarly, the capacity of PBMCs to produce IFN-γ was also significantly increased (p<0.001) depicting xii the promising nature of IL-6 in enhancing lymphocyte effector function. Overall the study concludes that IL-6 has an immense potential in rescuing PBMCs population, however IL 6 alone is not sufficient to sustain the adaptive immunity. It could be used as a potent candidate in combination with other regulatory factors for ex-vivo enhancement of lymphocyte and may help in moving one step towards adoptive T cell therapy in chronic HCV infection.