Negative control of mast cell degranulation and the anaphylactic response by the phosphatase lipin1.
Mast cells play a critical role in the pathogenesis of allergic diseases; however, how mast cell function is regulated is still not well understood. Both phosphatidic acid (PA) and diacylglycerol (DAG) are important secondary messengers involved in mast cell activ-ation. Lipin1 is a phosphatidate phosphatase that hydrolyzes PA to produce DAG, but the role of lipin1 in mast cell function has been thus far unknown. Here we show that lipin1 is an important and selective inhibitor of mast cell degranulation. Lipin1 deficiency enhanced FcεRI-mediated β-hexosaminidase and prostaglandin D2 release from mast cells in vitro and exacerbated the passive systemic anaphylaxis reaction in vivo. Lipin1 deficiency, however, did not exert obvious effects on IL-6 or TNF-α production following FcεRI engagement. FcεRI-induced PKC and SNAP-23 phosphorylation were augmented in the lipin1-deficient mast cells. Moreover, inhibition of PKC activity reduced SNAP-23 phosphorylation and mast cell degranulation in lipin1-deficient mast cells. Together, our findings suggest that lipin1 may negatively control mast cell degranulation and the anaphylactic response through inhibiting the PKC-SNAP-23 pathway.
Division of Allergy and Immunology, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Jinwook
J
Shin
Ping
P
Zhang
Shang
S
Wang
Jinhong
J
Wu
Ziqiang
Z
Guan
Xiao-Ping
XP
Zhong
D000707:Anaphylaxis / Q000276:immunology*; D000818:Animals; D015550:Cell Degranulation / Q000187:drug effects; D002478:Cells, Cultured; D007165:Immunosuppression Therapy; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology*; D010711:Phosphatidate Phosphatase / Q000235:genetics / Q000276:immunology*; D010766:Phosphorylation / Q000235:genetics; D015230:Prostaglandin D2 / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D050766:Qb-SNARE Proteins / Q000378:metabolism; D050767:Qc-SNARE Proteins / Q000378:metabolism; D017455:Receptors, IgE / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D009687:Nuclear Proteins; D050766:Qb-SNARE Proteins; D050767:Qc-SNARE Proteins; D017455:Receptors, IgE; C107017:Snap23 protein, mouse; D011493:Protein Kinase C; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase; D001619:beta-N-Acetylhexosaminidases; D015230:Prostaglandin D2