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Intradermal Administration of Thymic Stromal Lymphopoietin Induces a T Cell- and Eosinophil-Dependent Systemic Th2 Inflammatory Response

Heidi K. Jessup^*, Avery W. Brewer, Miyuki Omori, Erika A. Rickel^*, Alison L. Budelsky^*, Bo-Rin Park Yoon^*, Steven F. Ziegler and Michael R. Comeau^1,*

^* Inflammation Research, Amgen, Seattle, WA 98119; MedImmune, Gathersburg, MD 20878; Laboratory for Immune Regulation, Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan; and Department of Immunology, Benaroya Research Institute, Virginia Mason Medical Center, Seattle, WA 98101

The epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) is sufficient to induce asthma or atopic dermatitis-like phenotypes when selectively overexpressed in transgenic mice, or when driven by topical application of vitamin D3 or low-calcemic analogues. Although T and B cells have been reported to be dispensable for the TSLP-induced inflammation in these models, little is known about the downstream pathways or additional cell types involved in the inflammatory response driven by TSLP. To characterize the downstream effects of TSLP in vivo, we examined the effects of exogenous administration of TSLP protein to wild-type and genetically deficient mice. TSLP induced a systemic Th2 inflammatory response characterized by increased circulating IgE and IgG1 as well as increased draining lymph node size and cellularity, Th2 cytokine production in draining lymph node cultures, inflammatory cell infiltrates, epithelial hyperplasia, subcuticular fibrosis, and up-regulated Th2 cytokine and chemokine messages in the skin. Responses to TSLP in various genetically deficient mice demonstrated T cells and eosinophils were required, whereas mast cells and TNF- were dispensable. TSLP-induced responses were significantly, but not completely reduced in IL-4- and IL-13-deficient mice. These results shed light on the pathways and cell types involved in TSLP-induced inflammation.

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 Address correspondence and reprint requests to Michael R. Comeau, Amgen Inc., 1201 Amgen Court West, Seattle, WA 98119. E-mail address: comeaumr{at}amgen.com

² Abbreviations used in this paper: AD, atopic dermatitis; C_T, cycle threshold; DC, dendritic cell; DLN, draining lymph node; KO, deficient; MC, mast cell; MSA, mouse serum albumin; TSLP, thymic stromal lymphopoietin; WT, wild type.

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