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

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.

• Authors: Roberto Adachi, Steven A Krilis, Peter A Nigrovic, Matthew J Hamilton, Kyungemee Chung, Shakeel M Thakurdas, Joshua A Boyce, Paul Anderson, Richard L Stevens
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 24 Pg. 20047-55 (Jun 08 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 22511759 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Dermatophagoides
• Carcinogens
• Cytokines
• Rasgrp4 protein, mouse
• ras Guanine Nucleotide Exchange Factors
• Tetradecanoylphorbol Acetate

Topics

• Animals
• Antigens, Dermatophagoides (toxicity)
• Arthritis, Experimental (genetics, metabolism, pathology, therapy)
• Asthma (chemically induced, genetics, metabolism, pathology)
• Carcinogens (pharmacology)
• Cells, Cultured
• Cytokines (genetics, metabolism, pharmacology)
• Inflammatory Bowel Diseases (genetics, metabolism, pathology, therapy)
• Mice
• Mice, Knockout
• Signal Transduction
• Tetradecanoylphorbol Acetate (pharmacology)
• ras Guanine Nucleotide Exchange Factors (genetics, metabolism)