Fractalkine/CX<inf>3</inf>CL1 production by human airway smooth muscle cells: Induction by IFN-γ and TNF-α and regulation by TGF-β and corticosteroids

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Journal Article
American Journal of Physiology - Lung Cellular and Molecular Physiology, 2004, 287 (6 31-6)
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Chemokine synthesis by airway smooth muscle cells (ASMC) may be an important process underlying inflammatory cell recruitment in airway inflammatory diseases such as asthma and chronic obstructive pulmonary disease (COPD). Fractalkine (FKN) is a recently described CX3C chemokine that has dual functions, serving as both a cell adhesion molecule and a chemoattractant for monocytes and T cells, expressing its unique receptor, CX3CR1. We investigated FKN expression by human ASMC in response to the proinflammatory cytokines IL-1β, TNF-α, and IFN-γ, the T helper 2-type cytokines IL-4, IL-10, and IL-13, and the fibrogenic cytokine transforming growth factor (TGF)-β. Neither of these cytokines alone had any significant effect on ASMC FKN production. Combined stimulation with IFN-γ and TNF-α induced FKN mRNA and protein expression in a time- and concentration-dependent manner. TGF-β had a significant inhibitory effect on cytokine-induced FKN mRNA and protein expression. Dexamethasone (10-8-10-6 M) significantly upregulated cytokine-induced FKN mRNA and protein expression. Finally, we used selective inhibitors of the mitogen-activated protein kinases c-Jun NH2-terminal kinase (JNK) (SP-610025), p38 (SB-203580), and extracellular signal-regulated kinase (PD-98095) to investigate their role in FKN production. SP-610025 (25 μM) and SB-203580 (20 μM), but not PD-98095, significantly attenuated cytokine-induced FKN protein synthesis. IFN-γ- and TNF-α-induced JNK phosphorylation remained unaltered in the presence of TGF-β but was inhibited by dexamethasone, indicating that JNK is not involved in TGF-β- or dexamethasone-mediated regulation of FKN production. In summary, FKN production by human ASMC in vitro is regulated by inflammatory and anti-inflammatory factors.
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