15-Lipoxygenase eicosanoids are the putative ligands for vanilloid receptors and peroxisome proliferator-activated receptors (PPARs)

Abstract

We read the article by Zhao et al. (1), which showed that epithelial 15-lipoxygenase 1 (15LO1) and its product 15-hydroxyeicosatetraenoic acid phosphatidylethanolamine interact with phosphatidylethanolamine-binding protein (PEBP1) to enhance MAPK signaling (ERK activation) in human airway epithelia. This can then be seen as an internal mechanism in airway epithelium for adjusting the gain settings of critical inflammatory pathways integral to asthma pathogenesis. However, this model rests critically on three assumptions: (i) Epithelial 15LO1 is the major form of 15LO1 and the source of 15S-hydroxyeicosatetraenoic acid (15S-HETE), (ii) metabolites or eicosanoids of 15LO1 such as 15S-HETE are not released extracellularly, and (iii) these eicosanoids do not influence MAPK signaling through any other receptor. The authors explicitly stated that “15HETE is not released extracellularly” and that “unlike other eicosanoids, 15LO1 does not appear to function through receptor-mediated mechanisms, and, indeed, no receptor has been identified.” In this model, all these signaling events (15LO1–15-hydroxyeicosatetraenoic acid-phosphatidylethanolamine-ERK) are direct and exclusively occur inside the airway epithelia. This is potentially misleading. First, a minor discrepancy in the data, whereby 15LO1 was nearly undetectable in fresh bronchial epithelia isolated from normal and air–liquid interface (ALI)-cultured human bronchial epithelial cells without IL-13 induction [figures 1a and 2b (1)] but strongly expressed even without IL-13 stimulation in other supposed ALI epithelial cultures [figure 6a (1)], could be secondary to possible contamination of ALI cultures with macrophages. It has been reported that macrophages are also important sources of 15LO1 and 15(S)-HETE in the airway, with uptake and incorporation of 15(S)-HETE by epithelial cells (2). As their Materials and Methods (1) did not report the use of any technique to confirm the purity of isolated airway epithelia or cultured epithelia and to exclude macrophage contamination, we wonder if this possibility has been excluded. Second, eicosanoids of 15LO1, including 15S-HETE, have been found in biological fluids such as BAL fluid supernatants and sputum supernatants (2), indicating they also could be secretory with an extracellular role. Third, eicosanoids of 15LO directly bind with vanilloid receptors and PPARs (3, 4), indicating that 15S-HETE also could lead to receptor-mediated signaling for MAPK activation. TRPV1, one of the vanilloid receptors that may be important in refractory asthma, was found to be expressed in bronchial epithelia rather than macrophages, which indicates a possible crosstalk between macrophage and epithelium through secreted 15S-HETE from macrophages. Indeed, 15S-HETE has been considered as a 15LO2 metabolite rather than a 15LO1 metabolite (13S-HODE) (4), which is contradictory to the title of the article by Zhao et al. (1). Exogenous induction with metabolites of 15LO1 and 15LO2 differentially regulate MAPK signaling involving PPAR (4).