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An IL-17F/A Heterodimer Protein Is Produced by Mouse Th17 Cells and Induces Airway Neutrophil Recruitment

Spencer C. Liang^1,*, Andrew J. Long^2,*, Frann Bennett^*, Matthew J. Whitters^*, Riyez Karim, Mary Collins^*, Samuel J. Goldman^*, Kyriaki Dunussi-Joannopoulos^*, Cara M. M. Williams^*, Jill F. Wright^3,* and Lynette A. Fouser^3,4,*

^* Inflammation and Biological Technologies, Wyeth Research, Cambridge, MA 02140

IL-17A and IL-17F are related homodimeric proteins of the IL-17 family produced by Th17 cells. In this study, we show that mouse Th17 cells also produce an IL-17F/A heterodimeric protein. Whereas naive CD4⁺ T cells differentiating toward the Th17 cell lineage expressed IL-17F/A in higher amounts than IL-17A/A homodimer and in lower amounts than IL-17F/F homodimer, differentiated Th17 cells expressed IL-17F/A in higher amounts than either homodimer. In vitro, IL-17F/A was more potent than IL-17F/F and less potent than IL-17A/A in regulating CXCL1 expression. Neutralization of IL-17F/A with an IL-17A-specific Ab, and not with an IL-17F-specific Ab, reduced the majority of IL-17F/A-induced CXCL1 expression. To study these cytokines in vivo, we established a Th17 cell adoptive transfer model characterized by increased neutrophilia in the airways. An IL-17A-specific Ab completely prevented Th17 cell-induced neutrophilia and CXCL5 expression, whereas Abs specific for IL-17F or IL-22, a cytokine also produced by Th17 cells, had no effects. Direct administration of mouse IL-17A/A or IL-17F/A, and not IL-17F/F or IL-22, into the airways significantly increased neutrophil and chemokine expression. Taken together, our data elucidate the regulation of IL-17F/A heterodimer expression by Th17 cells and demonstrate an in vivo function for this cytokine in airway neutrophilia.

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 Current address: Cell Genesys, 500 Forbes Boulevard, South San Francisco, CA 94080.

² Current address: Pharmacology Abbott Bioresearch Center, 100 Research Drive, Worcester, MA 01605.

³ J.F.W. and L.A.F. contributed equally to this work.

⁴ Address correspondence and reprint requests to Drs. Lynette A. Fouser and Jill F. Wright, Wyeth Research, 87 Cambridge Park Drive, Cambridge, MA 02140. E-mail addresses: lfouser{at}wyeth.com and jwright{at}wyeth.com

⁵ Abbreviation used in this paper: BAL, bronchoalveolar lavage.

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