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IL-9 Promotes IL-13-Dependent Paneth Cell Hyperplasia and Up-Regulation of Innate Immunity Mediators in Intestinal Mucosa ¹

Valérie Steenwinckel^*,, Jamila Louahed^*,, Muriel M. Lemaire^*,, Caroline Sommereyns^*,, Guy Warnier^*, Andrew McKenzie, Frank Brombacher, Jacques Van Snick^*, and Jean-Christophe Renauld^2,*,

^* Ludwig Institute for Cancer Research, Brussels Branch, Brussels, Belgium; Experimental Medicine Unit, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium; Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge, United Kingdom; and University of Cape Town, Health Science Faculty, Institute of Infectious Disease and Molecular Medicine, Cape Town, South Africa

IL-9 contributes to lung inflammatory processes such as asthma, by promoting mast cell differentiation, B cell activation, eosinophilia, and mucus production by lung epithelial cells. The observation that IL-9 overexpressing mice show increased mast cell numbers in the intestinal mucosa suggests that this cytokine might also play a role in intestinal inflammation. In colons from IL-9 transgenic mice, the expression of Muc2, a major intestinal mucin gene, was up-regulated, together with that of CLCA3 chloride channel and resistin like , which are goblet cell-associated genes. Additional IL-9 up-regulated genes were identified and included innate immunity genes such as angiogenin 4 and the PLA2g2a phospholipase A₂, which are typical Paneth cell markers. Histochemical staining of Paneth cells by phloxine/tartrazine showed that IL-9 induces Paneth cell hyperplasia in Lieberkühn glands of the small intestine, and in the colonic mucosa, where this cell type is normally absent. Expression of Paneth cell markers, including angiogenin 4, PLA2g2a, and cryptdins, was induced in the colon of wild-type mice after two to four daily administrations of IL-9. By crossing IL-9 transgenic mice with IL-13^–/– mice, or by injecting IL-9 into IL-4R^–/– mice, we showed that IL-13 was required for the up-regulation of these Paneth cell-specific genes by IL-9. Taken together, our data indicate that Paneth cell hyperplasia and expression of their various antimicrobial products contribute to the immune response driven by TH2 cytokines, such as IL-9 and IL-13 in the intestinal mucosa.

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 the Belgian Federal Service for Scientific, Technical, and Cultural Affairs, by the Actions de Recherche Concertées of the Communauté Française de Belgique and the Opération Télévie.

² Address correspondence and reprint requests to Dr. Jean-Christophe Renauld, Ludwig Institute for Cancer Research and Experimental Medicine Unit, Université catholique de Louvain, Avenue Hippocrate 74, Brussels, Belgium. E-mail address: Jean-Christophe.Renauld{at}bru.licr.org

³ Abbreviations used in this paper: Tg, transgenic; WT, wild type; PLA₂, phospholipase A₂; mMCP, mouse MCP; mCLCA3, mouse calcium-activated chloride channel 3; Ang4, angiogenin 4; Retnla, resistin-like .