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FAN Stimulates TNF-Induced Gene Expression, Leukocyte Recruitment, and Humoral Response¹

Anne Montfort,^* Bénédicte de Badts,^* Victorine Douin-Echinard,^* Pascal G. P. Martin, Jason Iacovoni, Caroline Nevoit, Nicole Therville,^* Virginie Garcia,^* Marie-Antoinette Bertrand, Marie-Hélène Bessières,^¶ Marie-Claude Trombe,^* Thierry Levade,^* Hervé Benoist,^* and Bruno Ségui^2*

^*U858 INSERM, Toulouse, France; Institut Fédératif de Recherche 31, Institut de Médecine Moléculaire de Rangueil, Toulouse, France; Laboratoire de Pharmacologie et Toxicologie, Institut National de la Recherche Agronomique, Toulouse, France; Université Paul Sabatier (Toulouse III), Faculté des Sciences Pharmaceutiques, Service d’Immunologie, Toulouse, France; and ^¶Service de Parasitologie-Mycologie, Centre Hospitalier Universitaire Rangueil, Toulouse, France

Factor associated with neutral sphingomyelinase activation (FAN) is an adaptor protein that constitutively binds to TNF-R1. Microarray analysis was performed in fibroblasts derived from wild-type or FAN knockout mouse embryos to evaluate the role of FAN in TNF-induced gene expression. Approximately 70% of TNF-induced genes exhibited lower expression levels in FAN-deficient than in wild-type fibroblasts. Of particular interest, TNF-induced expression of cytokines/chemokines, such as IL-6 and CXCL-2, was impaired in FAN-deficient cells. This was confirmed by real time RT-PCR and ELISA. Upon i.p. TNF or thioglycollate injection, neutrophil recruitment into the peritoneal cavity was reduced by more than 50% in FAN-deficient mice. Nevertheless, FAN-deficient animals did not exhibit an increased susceptibility to different microorganisms including bacteria and parasites, indicating that FAN is not essential for pathogen clearance. Specific Ab response to BSA was substantially impaired in FAN-deficient mice and this was associated with a reduced content of leukocytes in the spleen of BSA-challenged FAN-deficient mice as compared with their wild-type counterparts. Altogether, our results indicate the involvement of FAN in TNF-induced gene expression and leukocyte recruitment, contributing to the establishment of the specific immune response.

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 study was supported by INSERM, Paul Sabatier University, Génopôle Toulouse-Midi-Pyrénées, Grant 3417 from the Association pour la Recherche sur le Cancer (to B.S.).

² Address correspondence and reprint requests to Dr. Bruno Ségui, Inserm U858, Institut de Médecine Moléculaire de Rangueil, BP 84225, 31432 Toulouse Cédex 4, France. E-mail address: bruno.segui{at}inserm.fr

³ Abbreviations used in this paper: TRADD, TNF-R1-associated protein with death domain; cdc42, cell division cycle 42; FAN, factor associated with neutral sphingomyelinase activation; FAN DN, dominant-negative FAN; IFA, incomplete Freund’s adjuvant; IPA, Ingenuity Pathways Analysis; MEF, mouse embryonic fibroblast; NSD, neutral sphingomyelinase domain.