CORESTA Congress, Quebec, 2014, Smoke Science/Product Technology Groups, ST 38

Role of oxidative stress in the suppression of immune responses in peripheral blood mononuclear cells exposed to combustible tobacco product preparations

ARIMILLI S.(1); DAMRATOSKI B.E.(1); PRASAD G.L.(2)
(1) Department of Microbiology & Immunology, Wake Forest University School of Medicine, Winston-Salem, NC, U.S.A.; (2) R.J. Reynolds Tobacco Company, R&D Department, Winston-Salem, NC, U.S.A.

Chronic cigarette smoking is known to adversely impact innate and adaptive immune responses, resulting in immunosuppression, which has been linked to increased susceptibility of smokers to microbial infections and higher incidences of cancer relative to non-smokers. We have shown that Whole Smoke-Conditioned Medium (WS-CM) from Kentucky 3R4F cigarettes potently suppressed agonist-stimulated cytokine secretion and target cell killing in Peripheral Blood Mononuclear Cells (PBMCs) in ex vivo cultures, whereas nicotine effects were minimal. Here we investigated the mechanisms of WS-CM induced suppression of select cytokine secretion in Toll-Like Receptor (TLR) agonist-stimulated cells and the cell killing by effector cells in PBMC population.

We investigated the relationship between the oxidative stress from cigarette smoke exposure and the observed suppression of the immune responses in PBMCs utilizing the ex vivo model. The addition of N-acetyl cysteine (NAC), a precursor of reduced glutathione and an established antioxidant, during exposure to WS-CM, resulted in reversing the adverse effects of WS-CM. The DNA damage and cytotoxicity due to exposure of WS-CM were reversed. Similarly, a recovery in secretion of IFN-γ, TNF, IL-10, IL-6 and IL-8 in response to TLR-4 stimulation was observed. The inhibition in target cell killing, a functional measure of cytolytic cells in PBMCs, by WS-CM was also restored by NAC. This was accompanied by augmentation of perforin levels in the effector cell populations. Consistent with our previous set of studies, nicotine treatment minimally impacted cytokine secretion and target cell killing, and addition of NAC did not modulate those responses. Collectively, these data suggest that the oxidative stress caused by WS-CM in PBMCs resulted in the suppression of receptor-mediated immune responses.