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*
Section on Chemical Immunology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
Perinatal Research Facility, Department of Obstetrics and Gynecology PHC-3, Georgetown University School of Medicine, Washington, DC 20012; and
Department of Microbiology and Immunology, Baylor College of Medicine, Houston, TX 77030
This study investigates whether the guanine nucleotide exchange
activity of Vav is linked to cytokine production in mast cells.
Overexpression of Vav in the RBL-2H3 mast cell line resulted in the
constitutive tyrosine phosphorylation and activation of Vav. We
analyzed the functional effect of Vav overexpression on cytokine
production. IL-2 and IL-6 mRNA levels were dramatically increased in
Vav-overexpressing cells and correlated with increased NF-AT activity.
Little or no effect was observed on the mRNA levels of IL-3, IL-4,
GM-CSF, TNF-
, and TGF-ß. Fc
RI engagement did not further
enhance IL-2 and IL-6 mRNA levels and only slightly enhanced NF-AT
activity, but dramatically increased the mRNA levels of other tested
cytokines. To understand the signal transduction required, we focused
primarily on IL-6 induction by measuring mitogen-activated protein
kinase activity and analyzing the effects of mutant or dominant
negative forms of Vav, Rac1, and c-Jun N-terminal kinase-1 (JNK1). Vav
overexpression resulted in the constitutive activation of JNK1 with
little or no effect on p38 mitogen-activated protein kinase and ERK2.
This was dependent on Vav-mediated activation of Rac1 as a Dbl
domain-mutated Vav, inactive Rac N17, and inactive JNK1 down-regulated
the Vav-induced JNK1 or IL-6 responses. Vav expression, but not
expression of domain-mutated Vav, increased IL-6 secretion from
nonimmortalized bone marrow-derived mast cells upon FcRI engagement.
We conclude that Vav phosphorylation contributes to IL-6 induction in
mast cells.
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