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IL-13 and IL-4 promote TARC release in human airway smooth muscle cells: role of IL-4 receptor genotype

¹Physiology Program, Harvard School of Public Health, Boston, Massachusetts 02115; ³Pulmonary, Allergy and Critical Care Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; and ²Laboratory of Respiration Physiology, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21949-900, Brazil

Submitted 17 April 2003 ; accepted in final form 14 July 2003

The chemokine thymus- and activation-regulated chemokine (TARC) induces selective migration of Th2, but not Th1, lymphocytes and is upregulated in the airways of asthmatic patients. The purpose of this study was to determine whether human airway smooth muscle (HASM) cells produce TARC. Neither IL-4, IL-13, IL-1, IFN-, nor TNF- alone stimulated TARC release into the supernatant of cultured HASM cells. However, both IL-4 and IL-13 increased TARC protein and mRNA expression when administered in combination with TNF- but not IL-1 or IFN-. Macrophage-derived chemokine was not expressed under any of these conditions. TARC release induced by TNF- + IL-13 or TNF- + IL-4 was inhibited by the -agonist isoproterenol and by other agents that activate protein kinase A, but not by dexamethasone. To determine whether polymorphisms of the IL-4R have an impact on the ability of IL-13 or IL-4 to induce TARC release, HASM cells from multiple donors were genotyped for the Ile50Val, Ser478Pro, and Gln551Arg polymorphisms of the IL-4R. Our data indicate that cells expressing the Val50/Pro478/Arg551 haplotype had significantly greater IL-13- or IL-4-induced TARC release than cells with other IL-4R genotypes. These data indicate that Th2 cytokines enhance TARC expression in HASM cells in an IL-4R genotype-dependent fashion and suggest that airway smooth muscle cells participate in a positive feedback loop that promotes the recruitment of Th2 cells into asthmatic airways.

asthma; tumor necrosis factor-; interleukin-1; interferon-; macrophage-derived chemokine; polymorphism; thymus- and activation-regulated chemokine

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