gp49B1 suppresses stem cell factor-induced mast cell activation-secretion and attendant inflammation in vivo.
We report that gp49B1, a mast cell membrane receptor with two immunoreceptor tyrosine-based inhibitory motifs (ITIM), constitutively inhibits mast cell activation-secretion induced by stem cell factor (SCF), a tissue-derived cytokine that also regulates mast cell development. The intradermal injection of SCF into the ears of gp49B1 null (gp49B(-/-)) mice elicited approximately 4- and 2.5-fold more degranulating mast cells and tissue swelling caused by edema, respectively, than in gp49B(+/+) mice. SCF did not induce tissue swelling in mast cell-deficient mice, and the responsiveness of gp49B(-/-) mice to mast cell-associated amine and lipid mediators was unaltered. When gp49B(+/+) and gp49B(-/-) mice were pretreated with antagonists of the amines, SCF-induced tissue swelling was reduced by >90% and 60%, respectively, and it was reduced by >90% in both genotypes when a cysteinyl leukotriene receptor antagonist was also provided. Hence, the dominant contribution of secretory granule amines to SCF-induced tissue swelling is the result of gp49B1-mediated inhibition of the production of cysteinyl leukotrienes by mast cells. Our findings also provide the first example of an ITIM-bearing receptor that constitutively suppresses inflammation generated in vivo independently of the adaptive immune response by a receptor that signals through intrinsic tyrosine kinase activity rather than immunoreceptor tyrosine-based activation motifs.
Feldweg
Anna M
AM
Department of Medicine, Harvard Medical School, Boston, USA.
Friend
Daniel S
DS
Zhou
Joseph S
JS
Kanaoka
Yoshihide
Y
Daheshia
Massoud
M
Li
Lin
L
Austen
K Frank
KF
Katz
Howard R
HR
D000818:Animals; D015550:Cell Degranulation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004487:Edema / Q000209:etiology / Q000276:immunology; D005260:Female; D007249:Inflammation / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology* / Q000502:physiology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008711:Metergoline / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000494:pharmacology; D019089:Stem Cell Factor / Q000494:pharmacology*; D014311:Triprolidine / Q000494:pharmacology
D002867:Chromones; C489447:Gp49a protein, mouse; C489448:Lilrb4 protein, mouse; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D008711:Metergoline; D014311:Triprolidine; C047681:pranlukast