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Am. J. Respir. Cell Mol. Biol., Volume 26, Number 2, February, 2002 202-208

The Th2 Lymphocyte Products IL-4 and IL-13 Rapidly Induce Airway Hyperresponsiveness Through Direct Effects on Resident Airway Cells

Rajeev Venkayya, Maggie Lam, Madeleine Willkom, Gabriele Grünig, David B. Corry, and David J. Erle

Lung Biology Center, Program in Immunology, and Cardiovascular Research Institute, University of California, San Francisco, California; Department of Pathology, St. Luke's-Roosevelt Hospital and Columbia University, New York, New York; and Department of Medicine, Baylor College of Medicine, Houston, Texas

Airway inflammation and airway hyperresponsiveness (AHR) are hallmarks of asthma. Cytokines produced by T helper type 2 (Th2) lymphocytes have been implicated in both processes. There is strong support for the idea that Th2 cytokines can produce AHR indirectly by promoting the recruitment of inflammatory cells. Less attention has been given to the possibility that Th2 cytokines might induce AHR by acting directly on resident airway cells. To investigate this, we polarized and activated CD4+ T cells in vitro and analyzed airway function after administration of lymphocyte-conditioned media to the airways of naive mice. Th2-lymphocyte-conditioned medium induced AHR within 6 h. This finding was reproduced in mast-cell-deficient and in T- and B-lymphocyte-deficient mice. AHR did not occur when Th2-lymphocyte-conditioned medium was administered to mice lacking the IL-4 receptor alpha  subunit or Stat6, suggesting a critical role for interleukin (IL)-4 and/or IL-13. This was confirmed by the finding that recombinant IL-4 and IL-13 both induced AHR within 6 h. The induction of AHR occurred in the absence of inflammatory cell recruitment or mucus production. These results strongly suggest that products of activated Th2 lymphocytes can rapidly perturb airway function through direct effects on resident airway cells.

Abbreviations: airway hyperresponsiveness, AHR; bronchoalveolar lavage, BAL; bronchoalveolar lavage fluid, BALF; interleukin, IL; IL-4 receptor alpha  subunit, IL-4Ralpha ; major basic protein, MBP; Periodic Acid-Schiff, PAS; phosphate-buffered saline, PBS; concentration of acetylcholine required to produce a 200% increase in resistance, PC200; T helper type 1, Th1; T helper type 2, Th2.




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