PLA2 phosphorylation and cyclooxygenase-2 induction, through p38 MAP kinase pathway, is involved in the IL-1β-induced bradykinin B2 receptor gene transcription

Abstract

We hypothesized that inflammatory mediators such as interleukin-1beta (IL-1beta) might be responsible for the hyperreactivity to bradykinin observed in asthmatic patients. We reported previously that IL-1beta induced a prostanoid-dependent increase in the density of bradykinin B2 receptors in cultured human bronchial smooth muscle cells. Our experiments demonstrate that the rapid prostaglandin E2 (PGE2) synthesis induced by IL-1beta is abolished by cycloheximide, suggesting the involvement of protein synthesis. The formation of PGE2 is preceded by the phosphorylation of cPLA2 and the expression of cyclooxygenase-2 (Cox-2). The inhibition of p38 MAP kinase inhibited PGE2 synthesis, cPLA2 phosphorylation and abolished Cox-2 expression. The inhibition of Cox-2 expression correlated with a decrease of bradykinin B2 receptor expression. These data demonstrate that the activation of p38 MAP kinase elicited by IL-1beta leads to the phosphorylation of cPLA2 and Cox-2 overexpression, allowing rapid synthesis of PGE2 as a prerequisite for bradykinin B2 gene expression in human bronchial smooth muscle cells which could explain the hyperresponsiveness of asthmatic patients to bradykinin.

Effects of Prostaglandin F2αand Carbachol on MAP Kinases, Cytosolic Phospholipase A2and Arachidonic Acid Release in Cat Iris Sphincter Smooth Muscle Cells

“…Recently, it has been shown in neutrophils stimulated with granulocyte/macrophage colony-stimulating factor (GM-CSF) that multiple signaling pathways act in parallel to phosphorylate cPLA 2 , in which both ERK kinases and p38 MAP kinases are involved (Geijsen et al, 2000). In human bronchial smooth muscle cells, interleukin-1b-induced PGE 2 formation is preceded by phosphorylation of cPLA 2 and expression of cyclooxygenase-2 (COX-2), and inhibition of p38 MAP kinase blocked cPLA 2 phosphorylation, COX-2 expression, and PGE 2 synthesis (Schmidlin et al, 2000). Fig.…”

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

“…Increased kinin formation has been demonstrated in pulmonary exudates during allergic reactions in humans (Proud et al, 1983;Naclerio et al, 1988). In addition, BK administration to airways has been shown to induce bronchoconstriction in asthmatics, but not normals (Fuller et al, 1987;Polosa and Holgate, 1990), perhaps due to enhanced B 2 receptor expression 66 in this sensitized patient population (Schmidlin et al, 2000). BK challenge also produces sore throat and rhinitis , and these symptoms are blocked by the potent and selective B 2 receptor antagonist icatibant (Proud et al, 1995).…”

Depression has a Strong Relationship to Alterations in the Immune, Endocrine and Neural System

“…Also, both clinical [45,47] and experimental (animal) studies of depression have shown an increase in tissue concentration of PGE 2 [44]. IL-6, which is also associated with depression, seems to play a crucial role in synthesizing this prostaglandin [48,49], and PGE 2 is itself a potent stimulant for IL-6 production, potentially representing an inflammatory pathogenic loop that may be operating in depressed individuals. It has been shown that tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) attenuate the PGE 2 -synthesis, probably via inhibition of pro-inflammatory cytokines.…”