Tyrosine phosphorylation of Vav stimulates IL-6 production in mast cells by a Rac/c-Jun N-terminal kinase-dependent pathway

James S. Song, Hana Haleem-Smith, Ramachandran Arudchandran, Jorge Gomez, Patricia M. Scott, John F. Mill, Tse Hua Tan, Juan Rivera

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

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-α, and TGF-β, FcεRI 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 FRK2. This was dependent on Vav-mediated activation of Rac1 as a Db1 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 FcεRI engagement. We conclude that Vav phosphorylation contributes to IL-6 induction in mast cells.

Original languageEnglish (US)
Pages (from-to)802-810
Number of pages9
JournalJournal of Immunology
Volume163
Issue number2
StatePublished - Jul 15 1999

Fingerprint Dive into the research topics of 'Tyrosine phosphorylation of Vav stimulates IL-6 production in mast cells by a Rac/c-Jun N-terminal kinase-dependent pathway'. Together they form a unique fingerprint.

Cite this