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Human Basophils Secrete IL-3: Evidence of Autocrine Priming for Phenotypic and Functional Responses in Allergic Disease¹

Department of Medicine, Division of Allergy and Clinical Immunology at the Johns Hopkins Asthma and Allergy Center, Johns Hopkins University, Baltimore, MD 21224

Although IL-3 is commonly recognized for its growth factor-like activity, in vitro studies have long demonstrated a unique capacity for this cytokine to also augment the proinflammatory properties and phenotype of human basophils. In particular, basophils secrete mediators that are hallmarks in allergic disease, including vasoactive amines (e.g., histamine), lipid metabolites (e.g., leukotriene C₄), and cytokines (e.g., IL-4/IL-13), which are all markedly enhanced with IL-3 pretreatment. This priming phenomenon is observed in response to both IgE-dependent and IgE-independent stimulation. Additionally, IL-3 directly activates basophils for IL-13 secretion and enhanced CD69 expression, two markers that are elevated in allergic subjects. Lymphocytes are commonly thought to be the source of the IL-3 that primes for these basophil responses. However, we demonstrate herein for the first time that basophils themselves rapidly produce IL-3 (within 4 h) in response to IgE-dependent activation. More importantly, our findings definitively show that basophils rapidly bind and utilize the IL-3 they produce, as evidenced by functional and phenotypic activity that is inhibited in the presence of neutralizing anti-IL-3 receptor (CD123) Abs. We predict that autocrine IL-3 activity resulting from low-level IgE/FcRI cross-linking by specific allergen represents an important mechanism behind the hyperreactive nature of basophils that has long been observed in allergic disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by Grant AI 042221 (to J.T.S.) from the National Institute of Allergy and Infectious Diseases, National Institutes Health.

J.T.S. designed the research; A.P.B., K.L.C., and J.T.S. performed the research as well as collected and analyzed the data; J.T.S. drafted the manuscript with input from A.P.B. and K.L.C.; all authors checked the final version of the manuscript.

² Address correspondence and reprint requests to Dr. John T. Schroeder, Unit Office 2, The Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224. E-mail address: schray{at}jhmi.edu

³ Abbreviations used in this paper: BEC, basophil-enriched cells; PAG, PIPES/albumin/glucose; HPRT, hypoxanthine phosphoribosyltransferase; MFI, mean fluorescence intensity; RT, room temperature; PGN, peptidoglycan.