Regulation of Eicosanoid Synthesis by Secreted Phospholipase A2
The first rate-limiting step in the formation of the CysLTs and other eicosanoids is the release of arachidonic acid from membrane phospholipids that is regulated by the PLA2 enzymes. In addition to the cytosolic PLA2α (cPLA2α), several secreted PLA2s (sPLA2)s have been implicated in eicosanoid synthesis, and may preferentially direct eicosanoid production toward leukotriene synthesis. In humans, increased sPLA2 activity has been identified in nasal lavage fluid and in bronchoalveolar lavage (BAL) fluid following allergen challenge, but the identities of the sPLA2s were not characterized. We characterized sPLA2 gene expression in induced sputum cells of asthmatic patients with EIB, and found significant expression of sPLA2 in group II, X and IIA enzymes. In a subsequent study[44••] examining the identities of sPLA2s in BAL fluid of asthmatic and nonasthmatic patients, the sPLA2 groups IIA and X predominated, but only secreted phospholipase A2 group X (sPLA2-X) was elevated in association with lung function and eicosanoid formation in the airways (Fig. 2). It is notable that sPLA2-X is expressed predominantly in the airway epithelium[44••] as we recently found that transglutaminase 2 (TGM2) is increased in the airways of patients with EIB and serves as a regulator of sPLA2-X activity[18••] (Fig. 3). Since sPLA2-X is secreted and can act on other target cells such as eosinophils to initiate eicosanoid formation, we examined the effects of exogenous sPLA2-X on human eosinophils and found that sPLA2-X rapidly initiated CysLT formation in eosinophils in a manner that was dependent upon the enzymatic activity of the enzyme, but occurred via activation of p38 and c-Jun MAPK (JNK) and cPLA2α.[45•]In vivo, genetic deficiency of either sPLA2-V or sPLA2-X in a murine model of asthma attenuates the development of allergen-induced inflammation, mucus release, and AHR,[46,47] as does inhibition of human sPLA2-X that was inserted under the endogenous promoter in a mouse model. These findings suggest that sPLA2-X may serve as a key regulator of eicosanoid formation in the airways and that this enzyme is strongly implicated in features of AHR such as EIB.
Levels of sPLA2-X protein in BAL fluid in relation to asthma severity and lung function. The levels of sPLA2-X in BAL fluid normalized to total protein were higher in asthmatic patients relative to controls, with the largest difference in the severe asthma group relative to controls (a). The figure shows the medians and interquartile ranges. The levels of sPLA2-X were associated with lung function among asthmatic patients by regression analysis (b). BAL, bronchoalveolar lavage; sPLA2-X, secreted phospholipase A2 group X. Adapted from reference [44••].
Increase in sPLA2-X enzyme activity mediated by TGM2. Preincubation of recombinant human sPLA2-X with purified TGM2 from guinea pig liver (a) or with recombinant human TGM2 (b) causes an increase in the PLA2 activity of the sPLA2-X enzyme. Denaturing the TGM2 with heat (boiled) or inhibiting the activity of the enzyme by saturating the enzyme with N-carbobenzoxy-Gln-Gly (Inh) demonstrate that the in-vitro findings are due to the enzymatic activity of TGM2. sPLA2-X, secreted phospholipase A2 group X; TGM2, transglutaminase 2. Adapted from reference [18••].
Curr Opin Allergy Clin Immunol. 2012;12(1):42-48. © 2012 Lippincott Williams & Wilkins