Artocarpol A stimulation of superoxide anion generation in neutrophils involved the activation of PLC, PKC and p38 mitogen‐activated PK signaling pathways

Abstract

1 Artocarpol A (ART), a natural phenolic compound isolated from Artocarpus rigida, stimulated a slow onset and long-lasting superoxide anion generation in rat neutrophils, whereas only slightly activated the NADPH oxidase in a cell-free system. 2 Pretreatment of neutrophils with pertussis toxin (1 mg ml À1 ), 50 mM 2 0 -amino-3 0 -methoxyflavone (PD 98059), or 1 mM 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126) had no effect on ART-stimulated superoxide anion generation. ART (30 mM) did not induce extracellular signal-regulated kinase (ERK) phosphorylation. 3 4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole (SB 203580) markedly attenuated the ART-stimulated superoxide anion generation (IC 50 value of 4.370.3 mM). Moreover, ART induced p38 mitogen-activated PK (MAPK) phosphorylation and activation. 4 The superoxide anion generation in response to ART was also substantially inhibited in a Ca 2 þ -free medium, and by pretreatment with 1 mM 1-[6-((17b-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)-hexyl]-1H-pyrrole-2,5-dione (U-73122) and 100 mM 2-aminoethyldiphenyl borate (2-APB). ART (30 mM) stimulated the [Ca 2 þ ] i elevation in the presence or absence of external Ca 2 þ , and also increased the D-myo-inositol 1,4,5-trisphosphate formation. 5 2-[1-(3-Dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide (GF 109203X) greatly inhibited the ART-stimulated superoxide anion generation (IC 50 value of 7.871.0 nM). ART increased the recruitment of PKC-a, -bI, and -bII to the plasma membrane of neutrophils, and stimulated Ca 2 þ -dependent PKC activation in the cytosol preparation. 6 ART induced the phosphorylation of p47 phox , which was attenuated by GF 109203X. Moreover, ART evoked the membrane association of p47 phox , which was inhibited by GF 109203X and SB 203580. 7 These results indicate that the ART stimulation of superoxide anion generation involved the activation of p38 MAPK, PLC/Ca 2 þ , and PKC signaling pathways in rat neutrophils.

PGE2 inhibits apical K channels in the CCD through activation of the MAPK pathway

“…Data summarized in Fig. 1B Several studies showed that stimulation of PKC enhanced the activity of MAPK such as P38 and ERK (5,14,25) which have been shown to inhibit the SK channels (3). Thus we examined the role of P38 and ERK in mediating the effect of PGE 2 on the SK channels.…”

“…The effect of K intake on ERK and P38 MAPK phosphorylation is at least partially mediated by superoxide and related products because suppressing superoxide levels with tempol abolished the effect of low-K intake on P38 and ERK phosphorylation (3). It is also well-established that stimulation of PKC could activate MAPK in a variety of cells (5,14,25). Although the mechanism by which PKC activates MAPK is not completely understood, PKC could activate NADPH oxidase by phosphorylation of p47phox (6) and increase the superoxide generation that stimulates the phosphorylation of ERK and P38 MAPK (3).…”

Plant Polyphenols and Tumors: From Mechanisms to Therapies, Prevention, and Protection Against Toxicity of Anti-Cancer Treatments

“…By contrast, apigenin and kaempferol induce apoptosis in tumor cells through activation of their mitochondrial NADPH-oxidase and intracellular oxidative stress [106]. The plant polyphenol artocarpol A up-regulates NADPH-oxidase in neutrophils by stimulating of PKC activation through p38 mitogen-activated protein kinase phosphorylation [107].…”

Molecular Mechanisms of N-Formyl-Methionyl-Leucyl-Phenylalanine-Induced Superoxide Generation and Degranulation in Mouse Neutrophils: Phospholipase D Is Dispensable

“…Conventional PKC (cPKC), which is synergistically activated by DG and Ca 2ϩ in conjunction with phosphatidylserine (PS) (12,13), has been suggested to play a role in superoxide generation and degranulation (14,15). In addition, PI3K and MAPK are also suggested to be involved in these neutrophil events (16)(17)(18)(19)(20). Thus, the molecular mechanisms which regulate superoxide generation and degranulation are very complicated.…”