Ras guanine nucleotide-releasing protein-4 (RasGRP4) involvement in experimental arthritis and colitis

Roberto Adachi, Steven A. Krilis, Peter A. Nigrovic, Matthew J. Hamilton, Kyungemee Chung, Shakeel M. Thakurdas, Joshua A. Boyce, Paul Anderson, Richard L. Stevens

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

RasGRP4 (Ras guanine nucleotide-releasing protein-4) is an intracellular, calcium-regulated guanine nucleotide exchange factor and diacylglycerol/phorbol ester receptor expressed in mast cells (MCs) and their progenitors. To study the function of this signaling protein in inflammatory disorders, a homologous recombination approach was used to create a RasGRP4-null C57BL/6 mouse line. The resulting transgenic animals had normal numbers of MCs in their tissues that histochemically and morphologically resembled those in WT C57BL/6 mice. MCs could also be generated from RasGRP4-null mice by culturing their bone marrow cells in IL-3-enriched conditioned medium. Despite these data, the levels of the transcripts that encode the proinflammatory cytokines IL-1β and TNF-α were reduced in phorbol 12-myristate 13-acetate-treated MCs developed from RasGRP4-null mice. Although inflammation was not diminished in a Dermatophagoides farinae-dependent model of allergic airway disease, dextran sodium sulfate-induced colitis was significantly reduced in RasGRP4-null mice relative to similarly treated WT mice. Furthermore, experimental arthritis could not be induced in RasGRP4-null mice that had received K/BxN mouse serum. The latter findings raise the possibility that the pharmacologic inactivation of this intracellular signaling protein might be an effective treatment for arthritis or inflammatory bowel disease.

Original languageEnglish (US)
Pages (from-to)20047-20055
Number of pages9
JournalJournal of Biological Chemistry
Volume287
Issue number24
DOIs
StatePublished - Jun 8 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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