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IL-17A Controls IL-17F Production and Maintains Blood Neutrophil Counts in Mice¹

Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA

G-CSF, its receptor, and IL-17 receptor A (IL-17RA) are all required to maintain baseline neutrophil counts in mice. In this study, we tested whether IL-17F could compensate and maintain baseline neutrophil counts in the absence of IL-17A. Unlike the reduced neutrophil counts found in IL-17RA-deficient mice, neutrophil counts were mildly increased in IL-17A-deficient (Il17a^–/–) animals. There was no evidence for infection or altered neutrophil function. Plasma G-CSF and IL-17F levels were elevated in Il17a^–/– compared with wild-type mice. IL-17F was mainly produced in the spleen and mesenteric lymph nodes, but IL-23 was unaltered in Il17a^–/– mice. Instead, Il17a^–/– splenocytes differentiated with IL-6, TGF-β, and IL-23 ex vivo produced significantly more IL-17F in response to IL-23 than wild-type cells. Adding rIL-17A to Il17a^–/– splenocyte cultures reduced IL-17F mRNA and protein secretion. These effects were also observed in wild-type but not IL-17RA-deficient cells. We conclude that IL-17A mediated suppression of IL-17F production and secretion requires IL-17RA and is relevant to maintain the normal set point of blood neutrophil counts in vivo.

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 S.v.V. was supported by Deutsche Forschungsgemeinschaft Grant VI508/1-1 and K.L. by National Institutes of Health Grant HL 073361.

² Address correspondence and reprint requests to Dr. Sibylle von Vietinghoff, Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA. E-mail address: Sibylle{at}liai.org

³ Abbreviations used in this paper: ROR, retinoic acid receptor-related orphan receptor; for, forward; rev, reverse; MLN, mesenteric lymph node.

⁴ The online version of this article contains supplemental material.

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				E. Smith, S. von Vietinghoff, M. A. Stark, A. Zarbock, J. M. Sanders, A. Duley, J. Rivera-Nieves, T. P. Bender, and K. Ley T-Lineage Cells Require the Thymus but Not V(D)J Recombination to Produce IL-17A and Regulate Granulopoiesis In Vivo J. Immunol., November 1, 2009; 183(9): 5685 - 5693. [Abstract] [Full Text] [PDF]