title: 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.affiliation: Department of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Adachi
authors.forename: Steven A
authors.initials: SA
authors.lastname: Krilis
authors.forename: Peter A
authors.initials: PA
authors.lastname: Nigrovic
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hamilton
authors.forename: Kyungemee
authors.initials: K
authors.lastname: Chung
authors.forename: Shakeel M
authors.initials: SM
authors.lastname: Thakurdas
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Boyce
authors.forename: Paul
authors.initials: P
authors.lastname: Anderson
authors.forename: Richard L
authors.initials: RL
authors.lastname: Stevens
mesh_terms: D000818:Animals; D039741:Antigens, Dermatophagoides / Q000633:toxicity; D001169:Arthritis, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D001249:Asthma / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002273:Carcinogens / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D020663:ras Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D039741:Antigens, Dermatophagoides; D002273:Carcinogens; D016207:Cytokines; C477240:Rasgrp4 protein, mouse; D020663:ras Guanine Nucleotide Exchange Factors; D013755:Tetradecanoylphorbol Acetate