Effect of nicotine on IL-18-initiated immune response in human monocytes

Abstract

Nicotine is thought to inhibit the production of proinflammatory cytokines from macrophages through an anti-inflammatory pathway that is dependent on nicotinic acetylcholine receptor alpha7 subunit (alpha7-nAChR). IL-18, an important proinflammatory cytokine, is reported to induce the expression of adhesion molecules on monocytes, thus enhancing cell-to-cell interactions with T-cells and contributing to IL-18-initiated cytokine production. Accordingly, inhibition of IL-18 suppresses systemic inflammatory responses. In the present study, we found that nicotine inhibited the IL-18-enhanced expression of ICAM-1, B7.2, and CD40 on monocytes, and the production of IL-12, IFN-gamma, and TNF-alpha by PBMC. A nonselective and a selective alpha7-nAChR antagonist, mecamylamine, and alpha-bungarotoxin abolished the effects of nicotine, suggesting that this depends on alpha7-nAChR stimulation. It is reported that nicotine induces prostaglandinE2 (PGE(2)) production in PBMC through the up-regulation of cyclooxygenase (COX)-2 expression. PGE(2) is known to activate the EP2/EP4-receptor, leading to an increase in cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity. Consistent with this, we found that COX-2 and PKA inhibitors prevented the effects of nicotine on adhesion molecule expression and cytokine production, indicating that the mechanism of action of nicotine may be via endogenous PGE(2) production.

Effect of Nicotine on Advanced Glycation End Product-Induced Immune Response in Human Monocytes

“…These results imply that the additional increase in PGE 2 by the combination of nicotine and AGEs might, at least partially account for the suppressive effect of nicotine on AGE-2-and AGE-3-induced enhancement of adhesion molecule expressions and cytokine production. We observed a similar pattern of inhibitory effects of nicotine on lipopolysaccharide (LPS)-and interleukin (IL)-18-induced activation of monocytes in human PBMCs via ␣7-nAChR Takahashi et al, 2006). Nicotine induced PGE 2 production in monocytes treated with LPS and IL-18 via ␣7-nAChR.…”

Activation of nicotinic acetylcholine receptor prevents the production of reactive oxygen species in fibrillar β amyloid peptide (1-42)-stimulated microglia

“…Besides Aβ neurotoxicity, another feature of AD is the loss of cholinergic projections and decline of nAChRs from the early stage of AD (Oddo and LaFerla, 2006). In this regard, recent studies have reported the existence of a cholinergic control of microglial activation by showing that nicotine reduced LPSinduced production of TNF-α and IL-18, indicating that nicotine has immunosuppressive effects (Shytle et al, 2004;De Simone et al, 2005;Suzuki et al, 2006;Takahashi et al, 2006). On the other hand, nicotine treatment significantly increased the expression of COX-2 and the synthesis of PGE2 in LPS-stimulated microglia, and even enhanced TNF-α production in BzATP-stimulated microglia, suggesting a neuroprotective effect of nicotine at low concentration (De Simone et al, 2005).…”

Essential Role of Osteopontin in Smoking-Related Interstitial Lung Diseases

“…Since several articles recently described an immuno-regulatory role of nicotine, [25][26][27] we tested if nicotine might influence OPN-production by alveolar macrophages. Therefore, we stimulated BAL-cells from healthy, currently smoking and nonsmoking individuals with nicotine.…”