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Interleukin-9 Induces Mucous Cell Metaplasia Independent of Inflammation

Center for Comparative Respiratory Biology and Medicine, University of California-Davis, Davis, California; Genentech Inc., South San Francisco, California; and Genaera Corporation, Plymouth Meeting, Pennsylvania

Address correspondence to: Dr. J. Rachel Reader, Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, 1 Shields Avenue, Davis, CA 95616-8734. E-mail: db4{at}pacbell.net

Interleukin-9 (IL-9) has been strongly implicated in the pathogenesis of asthma, including the overproduction of mucus, in humans and in animal models. We evaluated the inflammatory changes associated with the upregulation of mucus production by examining the time course of inflammation after daily intratracheal IL-9 administration to naive C57Bl6 mice for 9 d. IL-9 induced an asthmatic phenotype, which in general took several days to develop, as assessed by the measurement of airway hyperresponsiveness, pulmonary inflammation, and serum immunoglobulin E. However, within 24 h of a single dose of IL-9, muc5ac mRNA upregulation occurred, and increased numbers of periodic acid Schiff/Alcian blue-positive mucous cells appeared. This response occurred before the development of an inflammatory cell influx and was the result of epithelial metaplasia. It seemed that IL-9 evoked mucous cell metaplasia independent of IL-13 because mRNA tissue evaluation indicated that muc5ac upregulation preceded any increase in IL-13 mRNA expression or detectable levels of IL-13 in the brochoalveolar lavage fluid. Therefore, the upregulation of IL-13 by IL-9 may be responsible for the amplification of mucus production but is not required for its initiation. IL-9 seems to directly stimulate mucous cell metaplasia without the requirement of inflammatory cell influx.

Abbreviations: airway hyperresponsiveness, AHR • analysis of variance, ANOVA • airway pressure-time index, APTI • bronchoalveolar lavage, BAL • bronchoalveolar lavage fluid, BALF • bovine serum albumin, BSA • 5-chloro-2-deoxyuridine, Cldu • Dulbecco's phosphate-buffered saline, DPBS • 6-carboxyfluorescein, FAM • hematoxylin and eosin, H&E • 5-hydroxytryptamine, 5-HT • immunoglobulin E, IgE • interleukin, IL • intratrachael, IT • knock out, KO • lavage fluid protein, LFP • periodic acid Schiff/Alcian blue, PAS/AB • phosphate-buffered saline, PBS • reverse transcriptase/polymerase chain reaction, RT-PCR • 6-carboxy-N,N,N',N'-tetramethylrhodamine, TAMRA • white blood cells, WBC

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