Glutamine Prevents Late-Phase Anaphylaxis via MAPK Phosphatase 1-Dependent Cytosolic Phospholipase A2 Deactivation

Background: Cytosolic phospholipase A 2 (cPLA 2 ) plays a key role in the development of late-phase anaphylaxis. L -Glutamine (Gln), a nonessential amino acid, has anti-inflammatory activity via inhibiting cPLA 2 . Methods: We used a penicillin-induced murine model of anaphylaxis, and late-phase anaphylaxis was quantified by measuring the increase in the hematocrit (Ht) value. Various inhibitors, small interfering RNA, and knockout mice were used in inhibition experiments. Phosphorylation and protein expression of cPLA 2 , ERK, and MAPK phosphatase 1 (MKP-1) were detected by Western blotting. Results: Leukotriene (LT) B 4 was found to be another potent inducer of late-phase anaphylaxis besides the known mediator platelet-activating-factor (PAF). Gln efficiently prevented late-phase anaphylaxis when it was administered up to 3 h after challenge injection via inhibiting cPLA 2 . Inhibition studies indicated that p38 MAPK was the major upstream regulator of cPLA 2 . Gln dephosphorylated p38 and cPLA 2 via up-regulating the negative regulator of p38 MAPK, i.e., MKP-1 protein. MKP-1 blockade abrogated all the effects of Gln. Conclusion: Of the cPLA 2 metabolites, PAF and LTB 4 play a key role in the development of late-phase anaphylaxis, and Gln prevents the reaction via MKP-1-dependent deactivation of cPLA 2 .