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This Article Full Text Full Text (PDF) All Versions of this Article: 287/6/L1230    most recent 00014.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (14) Citing Articles via Google Scholar Google Scholar Articles by Sukkar, M. B. Articles by Chung, K. F. Search for Related Content PubMed PubMed Citation Articles by Sukkar, M. B. Articles by Chung, K. F.

Fractalkine/CX₃CL1 production by human airway smooth muscle cells: induction by IFN- and TNF- and regulation by TGF- and corticosteroids

Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College, SW3 6LY, London, United Kingdom

Submitted 20 January 2004 ; accepted in final form 12 August 2004

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-1, TNF-, and IFN-, the T helper 2-type cytokines IL-4, IL-10, and IL-13, and the fibrogenic cytokine transforming growth factor (TGF)-. Neither of these cytokines alone had any significant effect on ASMC FKN production. Combined stimulation with IFN- and TNF- induced FKN mRNA and protein expression in a time- and concentration-dependent manner. TGF- 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-- and TNF--induced JNK phosphorylation remained unaltered in the presence of TGF- but was inhibited by dexamethasone, indicating that JNK is not involved in TGF-- or dexamethasone-mediated regulation of FKN production. In summary, FKN production by human ASMC in vitro is regulated by inflammatory and anti-inflammatory factors.

chemokine; airway inflammation; asthma; chronic obstructive pulmonary disease

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