Nicotine Affects Immunity by Altering Notch Ligands on Dendritic Cells

OBJECTIVES: Epidemiological studies strongly indicate that tobacco use increases the risk of infectious diseases including gingivitis, periodontitis, and acute necrotizing ulcerative gingivitis. A potential mechanism whereby tobacco predisposes individuals to these diseases is through its effects on host responses to pathogens. Dendritic cells (DCs) are specialized cells that tailor host responses against pathogens by instructing the differentiation of T cells into Th1 and Th2 effector cells that mediate cellular and humoral immunity, respectively. In addition to the production of polarizing cytokines, DCs use the two notch ligand families, Delta and Jagged, to instruct Th1 and Th2 differentiation. Recently, we observed that DC exposed to nicotine, an immunomodulatory constituent of tobacco products, secrete less Th1-polarizing cytokine interleukin-12 and preferentially support the differentiation of Th2 effector cells. We analyzed the effects of nicotine on DCs further, by studying the expression of the notch ligands on these cells.

METHODS: DCs were generated by culturing DC precursors with GM-CSF (10ng/ml) and IL-4 (10ng/ml) in the absence (DC) or the presence of nicotine (nicDC, 100µg/mL). These cells were left intact or exposed to Th1-type stimuli, lipopolysacharride (LPS, 50ng/ml), or Th2-type stimuli, cholera toxin (1µg/ml) and prostaglandin E2 (PGE2, 10-6M) for 6hr. The gene expression of different notch ligands (Delta-1/Delta-4 and Jagged-1/Jagged-2) on these cells was examined by real-time qRT-PCR.

RESULTS: We found the expression of Delta-4 slightly reduced on nicDCs exposed to LPS, when compared to control DCs. We also observed an increase in the level of Jagged-1 expression. In addition, we found higher levels of Jagged-2 on nicDCs prior to and after stimulation with both Th1- and Th2-type stimuli, when compared to control DCs.

CONCLUSIONS: Our data suggest that nicotine compromises the host response to pathogens by affecting the expression of DC ligands involved in deciding the T-cell fate. Phillip Morris USA and International.