Cigarette smoke attenuates the production of cytokines by human plasmacytoid dendritic cells and enhances the release of IL-8 in response to TLR-9 stimulation

Esmaeil Mortaz, Zsofia Lazar, Leo Koenderman, Aletta D Kraneveld, Frans P Nijkamp, Gert Folkerts

Myeloid and plasmacytoid dendritic cells (mDCs, pDC) are crucial to the immune system, detecting microorganisms and linking the innate and adaptive immunity. pDC are present in small quantities in tissues that are in contact with the external environment; mainly the skin, the inner lining of the nose, lungs, stomach and intestines. They produce large amounts of IFN-alpha after stimulation and are pivotal for the induction of antiviral responses. Chronic obstructive pulmonary disease (COPD) patients are known to be more susceptible to viral infections. We have demonstrated that exposure of mDC to cigarette smoke extract (CSE) leads to the release of chemokines, however, not much is known about the role of pDC in COPD. In this study, we addressed several key questions with respect to the mechanism of action of CSE on human pDC in an in vitro model. Human pDCs were isolated from normal healthy volunteers and subjected to fresh CSE and the levels of IL-8, TNF-alpha, IP-10, IL-6, IL-1, IL-12 and IL-10 and IFN-alpha were studied by both ELISA and real time PCR methods. We observed that CSE augmented the production of IL-8 and suppressed the release of TNF-alpha, IL-6 and IFN-alpha. Moreover, CSE suppressed PI3K/Akt signalling in pDC. In conclusion, our data indicate that CSE has both the potential to diminish anti-viral immunity by downregulating the release of IFN-alpha and other pro-inflammatory cytokines while, at the same time, augmenting the pathogenesis of COPD via an IL-8 induced recruitment of neutrophils.