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Cigarette Smoke Synergizes Lipopolysaccharide-Induced InterIeukin-1β and Tumor Necrosis Factor–α Secretion from Macrophages via Substance P–Mediated Nuclear Factor–κB Activation

By Junyang Xu, Fadi Xu and Yong Lin


A recent study has indicated that alveolar macrophages from smokers incubated with lipopolysaccharide (LPS) secrete much more IL-1β and TNF-α than those from healthy nonsmokers, but the mechanisms underlying this augmented secretion by cigarette smoke (CS) remain unknown. CS and LPS reportedly promote macrophages' secreting substance P (SP) that could up-regulate these cytokines' secretion from macrophages by acting on neurokinin 1 receptor (NK1R). Moreover, NF-κB from macrophages participates in NK1R intracellular signaling and synthesis of these cytokines. The present in vitro study was undertaken to examine whether CS is able to synergize these cytokines' response to LPS in macrophages, and if so, whether an amplified SP secretion is responsible for this synergistic cytokines' response via a NK1R-driven NF-κB pathway. THP-1–derived and MH-S macrophages were exposed to control medium and CS condensate (CSC) without or with LPS. We found that LPS, CSC, and CSC+LPS significantly increased IL-1β, TNF-α, and SP secretion and that SP secretion markedly preceded cytokines' secretion. CSC+LPS-induced responses were markedly greater than the sum of the responses to CSC and LPS alone, suggesting a synergistic effect. Blocking NK1R reduced the responses of IL-1β, TNF-α, and NF-κB activation to CSC+LPS by 41, 40, and 46%, respectively. NF-κB inhibitors decreased the CSC+LPS–induced cytokines' responses by 70%. Our findings suggest that CS amplifies the LPS-induced macrophages' secretion of IL-1β and TNF-α through synergizing SP secretion, which activates NF-κB via binding with NK1R

Topics: Articles
Publisher: American Thoracic Society
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Provided by: PubMed Central
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