Interleukin‐1β and transforming growth factor‐β₂ enhance cytosolic high‐molecular‐mass phospholipase A₂ activity and induce prostaglandin E₂ formation in rat mesangial cells

Abstract

Interleukin-1P induces gene expression and secretion of group-I1 phospholipase A, and release of prostaglandin E2 from rat mesangial cells. The interleukin-lp-induced synthesis of group-I1 phospholipase A2 is prevented by transforming growth factor-/?,, whereas transforming growth factor-p2 potentiated the interleukin-lp-evoked prostaglandin E, production. Transforming growth factor-p, itself did not induce synthesis of group-I1 phospholipase A,, although it stimulated prostaglandin E2 formation. Here we describe the effect of interleukin-lp and transforming growth factorp2 on a cytosolic phospholipase A2 activity and prostaglandin E2 formation in rat mesangial cells.Based on the resistance to dithiothreitol and migration profiles on a Mono-Q anion-exchange column and a Superose 12 gel-filtration column, the cytosolic phospholipase A2 activity was assigned to a high-molecular-mass phospholipase A,. Measured with l-stearoyl-2-[1 -'4C]arachidonoylglycerophosphocholine as substrate, both interleukin-1p and transforming growth factor-pz enhanced the high-molecular-mass phospholipase A, activity. The stimulation of rat mesangial cells with interleukin-1 p and transforming growth factor-pz was time-and dose-dependent with maximal cytosolic phospholipase A, activities at 10 nM and at 10 ng/ml respectively, after 24 h of stimulation. Under these conditions, interleukin-1 p and transforming growth factor-p2 enhanced the cytosolic phospholipase A, activity 2.2 f 0.6-fold and 2.5 f 0.6-fold, respectively. These results strongly suggest that an enhanced cytosolic high-molecular-mass phospholipase A, activity is involved in the formation of prostaglandin E, mediated by transforming growth factor-p2. Whether interleukin-lp induced group-I1 phospholipase A, and/or interleukin-lp-enhanced cytosolic phospholipase A, activity is involved in prostaglandin E2 formation in rat mesangial cells is discussed.Phospholipase A, (PLA2) are a diverse family of important enzymes which have attracted considerable attention because of their role in the production of potent inflammatory mediators such as prostaglandins, leukotrienes and plateletactivating factor [ 11. Mammalian cells contain several PLA, enzymes including the 14-kDa enzymes and the more recently described high-molecular-mass enzymes. The 14-kDa PLA2s can be discriminated into group I and group I1 based on their primary structure [2]. Despite the potential importance of the PLA2s in lipid inflammatory mediator production, little is known about the type of PLA, involved.We and others have previously shown that the pro-inflammatory cytokines interleukin-1P (IL-1p) and tumor necrosis factor stimulate the synthesis and secretion of group-I1 PLA, Correspondence to H. van

Potentiation of Tumor Necrosis Factor α-induced Secreted Phospholipase A2 (sPLA2)-IIA Expression in Mesangial Cells by an Autocrine Loop Involving sPLA2 and Peroxisome Proliferator-activated Receptor α Activation

“…Interestingly, the expression of sPLA 2 -IIA induced by TNF␣ was only weakly reduced by pyrrolidine-1, although proinflammatory cytokines are known to produce a delayed activation of cPLA 2 in rat mesangial cells (51,52). This suggests that the delayed activation of cPLA 2 is not a major route in the TNF␣ signaling pathway leading to sPLA 2 -IIA expression.…”

“…In this regard, cytokines differ significantly and cause a delayed increase in cPLA 2 by up-regulating its mRNA expression (51,52). To elucidate whether cPLA 2 activation is involved in sPLA 2 -IIA expression, we analyzed the effect of pyrrolidine-1, a recently characterized specific inhibitor of cPLA 2 ␣ (53, 54).…”

Characteristics of lysophospholipase activity expressed by cytosolic phospholipase A2

“…sion was also documented in certain cytokine-treated cells (Schalkwijk et al, 1992, Nakamura et al, 1992Lin et al, 1992b). It was reported previously that cPLA, prepared from the mouse macrophage-like cell line, RAW264.7, apparently exhibited both phospholipase A, and lysophospholipase activities (Leslie, 1991), although the activity of phospholipase A, was about 10% that of phospholipase A,.…”

Elevated cPLA2 levels as a mechanism by which the p70 TNF and p75 NGF receptors enhance apoptosis

“…Agonists, such as thrombin, platelet-derived growth factor, epidermal growth factor and ATP [16][17][18], plus the serine kinases protein kinase C (PKC) and mitogen-activated protein (MAP) kinase, were shown to phosphorylate and activate cPLA z [19,20]. Furthermore, it has been shown that cytokines, macrophage colony-stimulating factor can influence cPLA2 activity [21][22][23]. Cytokines, such as interleukin-lfl and *Corresponding author.…”