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* 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.
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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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