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and TNF-
and regulation by TGF-
and corticosteroids
1 Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom
* To whom correspondence should be addressed. E-mail: f.chung{at}imperial.ac.uk.
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 pro-inflammatory cytokines IL-1
, TNF-
and IFN-
, the Th2-type cytokines IL-4, IL-10 and IL-13 and the fibrogenic cytokine 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 cytokineinduced 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 N-terminal kinase (JNK) (SP610025),
p38 (SB203580) and extracellular regulated kinase (ERK) (PD98095) to investigate their role in FKN production. SP610025 (25µM) and SB203580 (20[[mu]M), but not PD98095, 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.
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