FAN stimulates TNF(alpha)-induced gene expression, leukocyte recruitment, and humoral response.
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.
U858 INSERM, Toulouse, France.
Anne
A
Montfort
Bénédicte
B
de Badts
Victorine
V
Douin-Echinard
Pascal G P
PG
Martin
Jason
J
Iacovoni
Caroline
C
Nevoit
Nicole
N
Therville
Virginie
V
Garcia
Marie-Antoinette
MA
Bertrand
Marie-Hélène
MH
Bessières
Marie-Claude
MC
Trombe
Thierry
T
Levade
Hervé
H
Benoist
Bruno
B
Ségui
D000818:Animals; D000917:Antibody Formation; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000276:immunology / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D010529:Peritoneal Cavity / Q000502:physiology; D011008:Pneumococcal Infections / Q000276:immunology* / Q000382:microbiology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013296:Streptococcus pneumoniae / Q000276:immunology; D014122:Toxoplasma / Q000276:immunology; D014123:Toxoplasmosis / Q000276:immunology* / Q000469:parasitology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; C491112:Nsmaf protein, mouse; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha