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

Abstract

mokine 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 CX 3C 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 Ϫ8 -10 Ϫ6 M) significantly upregulated cytokineinduced 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 M) and SB-203580 (20 M), 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 THERE IS NOW SUBSTANTIAL EVIDENCE suggesting that airway smooth muscle cells (ASMC), by virtue of their immunomodulatory functions, may be involved in regulating airway inflammatory responses in diseases such as asthma and chronic obstructive pulmonary disease (COPD). ASMC express adhesion molecules and synthesize many cytokines and chemokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-8, eotaxin, and RANTES. These mediators are critically implicated in the recruitment, survival, and activation of key effector cells, such as eosinophils, neutrophils, and T lymphocytes, in asthma and COPD (10).Fractalkine (FKN), also known as CX 3 C ligand 1 (CX 3 CL1), is a novel chemokine belonging to the CX 3 C chemokine family. FKN is a multidomain molecule expressed on the cell surface and consists of a transmembrane region and a heavily glycosylated mucin-like stalk that extends from the cell surface, holding the chemokine domain at its tip (5). FKN also exists as a soluble glycoprotein that is generated by proteolytic cleavage of the full-length molecule at a membrane-proximal site (27,32,55). The physiological relevance of membrane and soluble FKN is not known; however, it is cu...

The Role of Airway Smooth Muscle in the Pathogenesis of Airway Wall Remodeling in Chronic Obstructive Pulmonary Disease

“…Although TGF-␤ may play an important role in remodeling, it has antiinflammatory properties. For example, TGF-␤ inhibits fractalkine (CX 3 CL) release induced by TNF-␣ and IFN-␥ from airway smooth muscle cells (83).…”

Fraktalkine Produced by Airway Smooth Muscle Cells Contributes to Mast Cell Recruitment in Asthma

“…F ractalkine (FKN), 4 or CX3CL1, is a CX3C chemokine expressed as a membrane-bound form (1) by several cell types, including vascular smooth muscle cells (2,3). Recently, it has been shown that human airway smooth muscle cells (HASMC), also can produce FKN upon stimulation by proinflammatory cytokines (4).…”

“…Recently, it has been shown that human airway smooth muscle cells (HASMC), also can produce FKN upon stimulation by proinflammatory cytokines (4). FKN interacts with its unique receptor CX3CR1 (5) on monocytes, NK cells, and T cells and mediates both adhesion and migration of leukocytes.…”

Association study between the CX3CR1 gene and asthma

“…However, two coding SNPs (T280M and V249I) have been shown to affect risk to other diseases involving immune and inflammatory diseases. [19][20][21][22][23] Based on our observations that the CX3CR1 gene is less expressed in bronchial biopsies of asthmatic subjects, 6 its biological importance in the recruitment of leukocytes in the inflammatory sites 8,9,12 and its potential role in allergic asthma, 17,18 we hypothesize that CX3CR1 is a candidate gene in asthma pathogenesis. The aims of this study were to carry out an association study and a haplotypic analysis with selected SNPs in CX3CR1 gene in a founder effect familial asthmatic sample from northeastern Quebec.…”

“…9 A role for CX3CR1-FKN-mediated inflammation has been suggested in various inflammatory diseases including vascular injury, 15 atopic dermatitis 16 and allergic airway diseases. 17,18 To our knowledge, no genetic association study has been reported between CX3CR1 and asthma. However, two coding SNPs (T280M and V249I) have been shown to affect risk to other diseases involving immune and inflammatory diseases.…”