Tumour necrosis factor (cachectin) induces phospholipase A2 activity and synthesis of a phospholipase A2-activating protein in endothelial cells

Abstract

Tumour necrosis factor (TNF) is an important mediator of endotoxin-induced vascular collapse and other inflammatory reactions. Eicosanoids have been implicated in the pathogeensis of these responses. In order to explore further the potential interactions between TNF and eicosanoid metabolism in eliciting vascular responses, we studied the effects of TNF on the bovine endothelial cell line CPAE. TNF induced cellular retraction observed by light microscope. This morphological change was monitored by the passage of iodinated protein A between adjacent cells and by release of [3H]arachidonic acid metabolites from cells. Both the morphological and functional responses were abrogated by inhibition of eicosanoid synthesis with BW755c. The release of [3H]arachidonic acid metabolites appeared to be mediated by a transient increase in phospholipase A2 activity. Phospholipase C activity was not affected by TNF. The maximal increase in phospholipase A2 activity occurred at 5 min following the addition of TNF. Phospholipase A2 activation, [3H]arachidonic acid-metabolite synthesis and passage of iodinated protein A, required both RNA and protein synthesis and were associated with an increase in the synthesis of a recently described phospholipase A2-activating protein. The Bordetella pertussis toxin, islet-activating protein, also inhibited the increase in phospholipase A2 activity, the release of [3H]arachidonic acid metabolites and the passage of iodinated protein A, suggesting that the TNF receptor-ligand interaction resulting in cellular retraction, phospholipase A2 activation and eicosanoid synthesis, is coupled through the Ni guanine nucleotide regulatory protein in these cells.

Prostaglandin Levels in Stimulated Macrophages Are Controlled by Phospholipase A2-activating Protein and by Activation of Phospholipase C and D

“…3B). These findings, in conjunction with the reported ability of PLAA to increase cytokine production (63)(64)(65), led to the possibility of an autocrine role of PLAA, which could result in perpetuating the inflammatory response. The rapid induction of the plaa gene in macrophages by LPS, IL-1␤, and TNF␣ coincided with an early increase in cPLA 2 and PGE 2 levels, with concomitant increases in the PLA 2 activity (Figs.…”

“…Reports that purified PLAA can induce synthesis of the proinflammatory cytokines IL-1␤ and TNF␣ led to the possibility that both an autocrine and paracrine loop can form, which would help perpetuate the aberrant immune response in IBD (7,(63)(64)(65). However, the purified PLAA used in the abovementioned studies was isolated using anti-melittin affinity chromatography and exhibited a size of 28 kDa, which probably represented a degraded version of the full-length PLAA (76).…”

Stimulatory and inhibitory guanine‐nucleotide‐binding regulatory protein involvement in stimulation of arachidonic‐acid release by N‐formyl‐methionyl‐leucyl‐phenylalanine and platelet‐activating factor from guinea‐pig alveolar macrophages

“…This phospholipase A, which exhibits several consensus sequences for serinet threonine protein kinases is translocated to the membrane when the Ca" concentration rises [51]. Whether this phospholipase or a regulatory protein (like the phospholipase activating protein [53]) might be directly or indirectly coupled to Met-Leu-Phe or PAF receptors by a G-protein-mediated process remains to be established.…”

Tumor Necrosis Factor-alpha as a possible auto-/paracrine factor affecting estrous cycle in the cat uterus

“…Skarzynski et al 2003) have proven that TNFα increased endometrial PG production, playing a role as an auto-/paracrine regulator of the endocrine events in the reproductive tract (von Wolff et al 1999). TNFα/TNFR1 complex has been demonstrated to activate PLA2 and, hence, increase PG secretion (Clark et al 1988). In the rat endometrium, TNFα affected both PGE 2 (Gamo et al 2007), and PGF 2α (Arslann and Zingg 1996).…”