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At least 469 records · Page 26Linked to original sources
PubMed2005

Intrathecal neostigmine reduces the zymosan-induced inflammatory response in a mouse air pouch model via adrenomedullary activity: involvement of spinal muscarinic type 2 receptors.

Intrathecal (IT) injection of neostigmine (a cholinesterase inhibitor) has been reported to produce a significant anti-nociceptive effect in a number of inflammatory pain models. However, a potential anti-inflammatory effect of IT neostigmine in these models has not been investigated. In the present study, we have examined the 'anti-inflammatory effect of IT injection of neostigmine' (AI-NEO) using a standard mouse air pouch model by evaluating the effect of AI-NEO on zymosan-induced leukocyte migration and myeloperoxidase (MPO) release. IT neostigmine was found to suppress both leukocyte migration and MPO degranulation in a dose dependent manner. We then established which subtypes of cholinergic receptors were involved in this AI-NEO. IT pretreatment with atropine (a muscarinic receptor antagonist) but not hexamethonium (a nicotinic receptor antagonist) completely blocked the IT neostigmine anti-inflammatory effect. Subsequent experiments showed that IT pretreatment with methoctramine (a muscarinic type 2 (M2) receptor antagonist), but not pirenzepine (M1 receptor antagonist) or 4-DAMP (M3 receptor antagonist), suppressed the AI-NEO. We then evaluated whether adrenal glandular activity was important in the AI-NEO. Adrenalectomy significantly blocked the AI-NEO, while intraperitoneal pretreatment with the beta-adrenoceptor antagonist (propranolol), but not the corticosteroid antagonist (RU486) reversed AI-NEO. In conclusion, these results indicate that IT neostigmine facilitates the activation of spinal M2 receptors and this activation ultimately leads to release of adrenal catecholamines which contribute to the anti-inflammatory effect observed at the site of tissue inflammation.

Adrenal Cortex Hormones↗
PubMed2003

Zymosan: induction of sickness behavior and interaction with lipopolysaccharide.

The yeast particulate zymosan (Zy) activates innate immune system cells and induces cytokine secretion. There is also evidence that Zy can affect biologic responses to bacterial lipopolysaccharide (LPS) and that the pathways by which these two agents act upon immune cells are only partially distinct. The present experiments assessed the ability of Zy to elicit CNS-mediated sickness symptoms and to alter their responses to LPS. In Experiment 1, Zy induced elements of the sickness behavior syndrome dose-responsively in Long-Evans rats, as indicated by reductions in consumption of a highly palatable bait and in body temperature. In Experiment 2, Zy exerted a priming effect, sensitizing animals to subsequent LPS as measured by reductions in bait consumption, 24-h laboratory chow intake, and body temperature. Experiment 3 failed to provide evidence for LPS-to-Zy cross-tolerance but did indicate that the administration of Zy disrupts previously acquired LPS tolerance. These results suggest that the specifics of exposure to microbially derived innate immune activators have to be taken into account in investigating the biologic bases of sickness behaviors and developing models of coinfection.

Analysis of Variance↗
PubMed2006

Peritoneal cavity phagocytes from the teleost sea bass express a glucocorticoid receptor (cloned and sequenced) involved in genomic modulation of the in vitro chemiluminescence response to zymosan.

To gain further insight into the role of cortisol in fish innate immune responses, we cloned and sequenced a 2592bp cDNA from sea bass (Dicentrarchus labrax) peritoneal leukocytes (PCLs) encoding a glucocorticoid receptor (DlGR1). The deduced aminoacid sequence displayed that DlGR1 belong to a multigenic family of steroid hormone receptors, and exhibited high homology (80%) to the Burton's mouth breeder (Haplochromis burtoni) HbGR1. The DlGR1 functional domains presented homologies with those of several vertebrate species. In situ hybridization assay revealed that DlGR1 was expressed in macrophages and neutrophils from the peritoneal cavity. Since in a previous paper, sea bass PCL chemiluminescence response (CL) has been related to increased respiratory burst of phagocytes stimulated with zymosan, PCLs, pre-incubated in vitro with cortisol at various concentrations, were assayed for their CL response. Dose-dependent cortisol inhibitory effects, and significant competitive activity of a low concentration of mifepristone (RU486), a glucocorticoid-receptor blocker, supported that cortisol-GR interaction was involved in modulating CL response via a genomic pathway. Results also indicated that cortisol could be effective through an additional not-genomic way, and showed that high doses of RU486 exerted an inhibitory effect on PCL chemiluminescence activity.

Amino Acid Sequence↗
PubMed1984

Chemotactic factor production by rat polymorphonuclear leukocytes: stimulation with opsonized zymosan particles and inhibition by dexamethasone.

Rat polymorphonuclear leukocytes exposed to opsonised zymosan particles in vitro instantaneously and continuously release a chemotactic factor in the medium. The activity of this factor was mainly attributed to leukotriene B4, based on the data with high performance liquid chromatography. Preincubation of the cells with an antiinflammatory steroid, dexamethasone, at a dose of 0.25 micrograms/ml caused suppression in generation of the chemotactic factor from the leukocytes in a time-dependent manner.

Animals↗
PubMed1996

Two chemotactic factors, C5a and MIP-1alpha, dramatically alter the mortality from zymosan-induced multiple organ dysfunction syndrome (MODS): C5a contributes to MODS while MIP-1alpha has a protective role.

Multiple organ dysfunction syndrome (MODS) is a major cause of morbidity and mortality in surgical intensive care units. It is characterized by progressive failure of two or more organs remote from the origin of injury. Since MODS results from a severe generalized inflammatory response, both chemokines and complement have had a proposed role in its pathophysiology. The availability of macrophage inflammatory protein 1 alpha (MIP-1alpha) knockout mice and congenic C5-deficient and C5-sufficient mice allowed us to investigate the individual contribution of these immune modulators in MODS. It has been demonstrated in this assay that MIP-1alpha has a protective role against MODS mortality, while C5a contributes to MODS mortality. Using a zymosan-induced MODS murine model, the absence of MIP-1alpha increased mortality four-fold, whereas the absence of C5 decreased mortality four-fold. Therefore, MIP-1alpha-dependent mediators are essential in the prevention of MODS related deaths, while C5-dependent mediators of inflammation can be considered to be contributing to the development of MODS related deaths.

Animals↗
PubMed2000

Delayed clearance of zymosan-induced granuloma and depressed phagocytosis of macrophages with concomitant up-regulated kinase activities of Src-family in a human monocyte chemoattractant protein-1 transgenic mouse.

A human monocyte chemoattractant protein-1 (hMCP-1) transgenic mouse (Tgm) line which constitutively produces a large amount of hMCP-1 (7-13 ng/ml in the serum) was established. Although expression of the transgene was detected in various tissues, an accumulation of macrophages (Mphi) was seen in only lymphoid organs which might be attributed to the high concentration of hMCP-1 in these organs. A reduced phagocytosis by peritoneal Mphi in vivo and a delayed clearance of granulomas in the liver following zymosan administration were observed in these Tgm. However, peritoneal exudate cells (PEC) from Tgm exhibited normal in vitro phagocytic activity and nitric oxide (NO) production upon stimulation with IFN-gamma as compared with those from non-Tgm. In addition, high activities of src-family protein tyrosine kinases (PTK), Fgr and Hck, were also noted in the peritoneal resident cells from Tgm, whereas the level of mitogen-activated protein kinase (MAPK) activity was almost the same as that of non-Tgm. It was suggested that the low functional activities of Tgm Mphi seen in vivo were attributed to down-regulation of the unique transducing system of hMCP-1 signals under the influence of a high concentration of the hMCP-1. It seemed that the depressed functions were recovered when the peritoneal cells were released ex vivo from such a high hMCP-1 environment.

Animals↗
PubMed1997

Chemiluminescence from human polymorphonuclear leukocytes activated with opsonized zymosan.

To prove the mechanism of photon emission during activation of leukocytes, a model system of human polymorphonuclear leukocytes (PMNs)-opsonized zymosan (OZ)-tyrosine (or none) or myeloperoxidase (MPO)-H2O2-tyrosine was employed, and three parameters-chemiluminescence yield and intensity, a metabolite such as bityrosine (BT), and chemiluminescence spectra-were studied. With the PMN system, the luminescence was enhanced by addition of tyrosine, its analogues, or albumin, but was inhibited by hydroxyurea, superoxide dismutase (SOD), or NaN3 (an inhibitor of MPO), indicating participation of tyrosine phenoxyl radicals, O2.- and MPO in the luminescence. With the PMN-OZ-tyrosine system, chemiluminescence yield was parallel to the BT formation. These results were essentially the same as those obtained with the MPO-H2O2-tyrosine system, except that luminescence from the latter system was not inhibited by SOD. When human albumin was exposed to the MPO-H2O2 system, BT was detected after hydrolysis of the protein in the mixture. Judging from the chemiluminescence spectra of activated PMNs and the MPO-catalyzed tyrosine oxidation, at least two excited species in triplet states-one for tyrosine and another for BT-would be generated in these systems. The luminescence may originate from the reaction of tyrosine phenoxyl radicals (cation radicals) with O2.- and/or peroxidase compound III (Fe...IIIO2.-).

Humans↗
PubMed1999

Inflammatory and immunopharmacological activities of meta-periodate oxidized zymosan.

Zymosan (ZYM), a strong complement-activating yeast cell preparation composed mainly of mannan and beta-glucan moieties, is a potent inflammatory substance with immunopharmacological activity. We previously analyzed the metabolism of ZYM in mice and found that it was deposited in liver and spleen for at least several months and then gradually oxidatively degraded. In this paper, we prepared oxidized ZYM by sodium metaperiodate oxidation (NaIO4) and borohydride reduction (I/B-ZYM) and/or limited hydrolysis of oxidized moieties (I/B/H-ZYM). Activities of the resulting products were assessed by (i) vascular permeability in mice, (ii) H2O2 synthesis by macrophages, (iii) TNF-alpha synthesis by macrophages, and (iv) reactivity to anti-ZYM sera. As a general trend, NaIO4, oxidation products exhibited reduced, but still significant, activity. Interestingly, the H2O2 production induced by I/B/H-ZYM was significantly reduced after extensive sonication. Antagonist(s) for H2O2 synthesis were concomitantly solubilized by sonication of I/B/H-ZYM. On the contrary, TNF-alpha production induced by I/B/H-ZYM was comparable with that of ZYM. These facts strongly suggest that highly branched 1,3-beta- and 1,6-beta-glucosidic linkages resistant to NaIO4 oxidation are important for biological activity of ZYM. Further, the minimal structure in ZYM necessary for biological activity may depend on the activity tested.

Animals↗
PubMed1997

Monocyte adherence to Paracoccidioides brasiliensis, zymosan-C3b and erythrocyte-hemolysin in patients with paracoccidioidomycosis.

Independent and dependent (C3b/Fc receptors) opsonic adherence ability of monocytes from thirty-three patients with acute or chronic paracoccidioidomycosis and from 13 healthy individuals were studied in the presence of Paracoccidioides brasiliensis (Pb), Paracoccidioides brasiliensis opsonized by patient's serum (PbPS) or normal serum (PbNS), zymosan opsonized by fresh sera from healthy donors (ZyNS) and erythrocytes opsonized by hemolysin (EA). Statistically significant differences concerning the percentage of adhered monocytes to PbPS (number of adhered monocytes/total number of monocytes) were detected between control and chronic (active and inactive) groups. Significant differences in relationship to the mean number of PbPS (number of fungi in monocytes/total number of monocytes) were also observed between control and chronic active mycosis. Present data suggest that patients with chronic disease have more ability in the first step of phagocytic activity, considered as the main effector mechanism to control the dissemination and severity of paracoccidiodomycosis.

Acute Disease↗
PubMed2000

Activation of human neutrophils with chemotactic peptide, opsonized zymosan and the calcium ionophore A23187, but not with a phorbol ester, is accompanied by efflux and store-operated influx of calcium.

The objective of this study was to monitor alterations in cellular Ca2+ metabolism following activation of neutrophils with receptor- (chemotactic peptide, FMLP, 1 microM; opsonized zymosan, OZ, 0.5 mg/ml) and non-receptor (calcium ionophore, A23187, 1 microM; phorbol 12-myristate 13-acetate, PMA, 25 ng/ml)-mediated stimuli of the pro-inflammatory functions of these cells. Ca2+ fluxes in activated neutrophils were measured using a fura-2-based spectrofluorimetric method in combination with radiometric (45Ca) procedures which facilitate distinction between net efflux and net influx of the cation. Exposure of neutrophils to receptor-mediated stimuli and to A23187 was associated with an abrupt increase in cytosolic Ca2+ coincident with a rapid efflux of the cation which terminated at around 30 s. In the case of FMLP and OZ, this was followed by a delayed (30-60 s), store-operated influx of Ca2+, which was complete at around 5 min after addition of the stimulus. With A23187, however, influx of Ca2+ occurred immediately following activation of the cells. There were no detectable alterations in cytosolic Ca2+ or measurable net efflux or influx of the cation above control levels in PMA-activated neutrophils. These data demonstrate that FMLP, OZ- and A23187-mediated alterations in neutrophil cytosolic Ca2+ are due to mobilization of both intracellular and extracellular cation, while activation of neutrophils by PMA is independent of alterations in cytosolic Ca2+.

Calcimycin↗
PubMed2001

The mechanisms of serum-treated zymosan (STZ)-induced oxidative metabolism by human eosinophils and the effects of IL-5 priming.

BACKGROUND: The aim of this work was to study the mechanisms of action of IL-5 on the subsequent stimulation of the oxidative metabolism of blood eosinophils by serum-treated zymosan (STZ), in terms of signal transduction characteristics, and by comparing the response of cells from healthy and allergic subjects during environmental exposure to birch pollen. METHODS: Eosinophils from healthy controls and allergic patients were purified to over 95% by Percoll gradients and the MACS system. Oxidative metabolism was measured by a lucigenin-enhanced chemiluminescence (CL) assay. Eosinophils were primed with IL-5 and subsequently stimulated with STZ. The signal transduction mechanisms of IL-5 priming were studied with the MEK inhibitor PD 98059,the PkC inhibitors staurosporine and Ro 318220, and the PI3 kinase inhibitor wortmannin. RESULTS: IL-5 increased the maximum radical production (P=0.0079) and reduced the t(1/2) rise (0.000018) of the CL reactions. The t(1/2) rise was PkC dependent and MEK independent, while the maximum radical production was PkC, MEK, and PI3 kinase dependent. During the pollen season, IL-5 reduced the total STZ-induced CL response in the patients' cells (P=0.016), but not in the control cells, whereas it primed the response to STZ of both cell populations in terms of the t(1/2) rise (P=0.012 and 0.00066, respectively). CONCLUSION: STZ-induced oxidative metabolism consists of different stages. The initial stage (t(1/2) rises of the curves) is PkC dependent and MEK independent, while the end stage (maximum radical production) is PkC, MEK, and PI3 kinase dependent. IL-5 shortened the initial stage, and increased the end stage. During allergen exposure, however, the end stage was reduced by IL-5. This could be due to increased amounts of hypodense eosinophils and/or some abnormality in cell responses.

Carrier Proteins↗
PubMed2003

Phagocytosis of serum- and IgG-opsonized zymosan particles induces apoptosis through superoxide but not nitric oxide in macrophage J774A.1.

Phagocytosis of serum- and IgG-opsonized zymosan (SOZ and IOZ, respectively) particles into J774A.1 macrophages induced apoptosis of the cells, accompanied by the expression of p21(WAF1), one of cyclin-dependent protein kinase (CDK) inhibitors. Furthermore, phagocytosis of SOZ and IOZ particles into macophages induced superoxide formation. Tat-superoxide dismutase (SOD), which is readily transduced into the cells using Tat-domain, protected the cells from the apoptosis induced by phagocytosis of SOZ and IOZ particles. lipopolysaccharide (LPS) /interferon-gamma (IFN-gamma) also caused the apoptosis of the cells. However, Tat-SOD could not protect the cells from LPS/IFN-gamma induced apoptosis, suggesting that apoptosis mechanisms involved are different from each other. In the present study, we determined the amounts of nitric oxide (NO) produced by SOZ, IOZ, and LPS/IFN-gamma, and found that SOZ and IOZ did not induce the generation of NO in macrophages, whereas LPS/ IFN-gamma did. The apoptosis due to phagocytosis was accompanied with the release of cytochrome c from mitochondrial membrane to cytosolic fraction. Furthermore, SOZ and IOZ induced the cleavage of procasapase-3 (35 kDa) to give rise to an active caspase-3 (20 kDa), which was blocked by Tat- SOD but not by 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (PTIO), a scavenger of NO. On the other hand, LPS/IFN-gamma caused the activation of procaspase-3, which was blocked by PTIO but not by Tat-SOD. Taken together, phagocytosis of SOZ and IOZ particles induced apoptosis through superoxide but not NO in macrophages, accompanied with the release of cytochrome c and the activation of caspase-3.

Apoptosis↗
PubMed2005

Downstream components of RhoA required for signal pathway of superoxide formation during phagocytosis of serum opsonized zymosans in macrophages.

Rac1 and Rac2 are essential for the control of oxidative burst catalyzed by NADPH oxidase. It was also documented that Rho is associated with the superoxide burst reaction during phagocytosis of serum- (SOZ) and IgG-opsonized zymosan particles (IOZ). In this study, we attempted to reveal the signal pathway components in the superoxide formation regulated by Rho GTPase. Tat-C3 blocked superoxide production, suggesting that RhoA is essentially involved in superoxide formation during phagocytosis of SOZ. Conversely SOZ activated both RhoA and Rac1/2. Inhibition of RhoA-activated kinase (ROCK), an important downstream effector of RhoA, by Y27632 and myosin light chain kinase (MLCK) by ML-7 abrogated superoxide production by SOZ. Extracellular signaling-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) were activated during phagocytosis of SOZ, and Tat-C3 and SB203580 reduced ERK1/2 and p38 MAPK activation, suggesting that RhoA and p38 MAPK may be upstream regulators of ERK1/2. Inhibition of ERK1/2, p38 MAPK, phosphatidyl inositol 3-kinase did not block translocation of RhoA to membranes, suggesting that RhoA is upstream to these kinases. Inhibition of RhoA by Tat-C3 blocked phosphorylation of p47(PHOX). Taken together, RhoA, ROCK, p38MAPK, ERK1/2, and p47(PHOX) may be subsequently activated, leading to activation of NADPH oxidase to produce superoxide.

Animals↗
PubMed1996

The effect of BCG, zymosan and Coxiella burnetti extract on Eimeria infections.

Infection of animals with species of Eimeria induces a hyper-reactivity to endotoxin as manifest by a greatly increased capacity of infected animals to produce TNF in response to LPS in vivo compared with uninfected animals. This finding indicates priming for hyperactivation of macrophages by Eimeria infection and raises the possibility that non-specific triggering of macrophages by agents such as Bacille Calmette-Guerin (BCG), zymosan or Coxiella burnetti extract may be a simple means of control for coccidiosis. However, all of these agents enhanced oocyst excretion in mice, rats or chickens infected with Eimeria vermiformis, Eimeria nieschulzi or Eimeria tenella, respectively, without affecting the patent period.

Animals↗
PubMed2002

Inhibition by prostaglandin E(2) of anaphylatoxin C5a- but not zymosan-induced prostanoid release from rat Kupffer cells.

The proinflammatory anaphylatoxin C5a induces the release of prostanoids, ie, prostaglandins (PG) and thromboxane (TX), from the resident liver macrophages (Kupffer cells [KC]). Because KC themselves express prostanoid receptors, prostanoids--besides having paracrine functions--might regulate their own release in an autocrine loop. So far, such a possible feedback regulation has not been investigated systematically, probably because of methodological difficulties to measure newly synthesized prostanoids in the presence of added prostanoids. Here, after prelabeling of phospholipids with [(14)C]arachidonate, cellularly formed [(14)C]prostanoids were determined in the presence of added unlabelled prostanoids by thin layer chromatography. In cultured KC, recombinant rat C5a (rrC5a) rapidly increased PGD(2), PGE(2), and TXA(2) release, which was strongly reduced by PGE(2), but neither by PGD(2) nor by the TXA(2) analog U46619. The inhibitory effect of PGE(2) was mimicked by cAMP, indicating that the G(s)-coupled PGE(2) receptors type 2 or 4 were involved. Zymosan also enhanced prostanoid release from KC, but with slightly slower kinetics; this action was neither inhibited by PGE(2) nor by cAMP. Also in perfused rat livers, rrC5a enhanced prostanoid release from KC as shown by prostanoid overflow and thereby indirectly increased glucose output from hepatocytes. Again, PGE(2), but not PGD(2), inhibited rrC5a-elicited prostanoid overflow. This resulted in a complete inhibition of rrC5a-induced, prostanoid-mediated glucose output. Thus, PGE(2) can inhibit specifically the C5a-induced prostanoid release from KC via a feedback mechanism and thereby limit prostanoid-mediated hepatocellular defense reactions, eg, glucose release.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1986

Arachidonic acid turnover in response to lipopolysaccharide and opsonized zymosan in human monocyte-derived macrophages.

Macrophages are an important source of the lipid mediators, arachidonic acid metabolites and platelet-activating factor (PAF), produced during inflammation. Studies were undertaken to identify the phospholipid substrates that can serve as a source of arachidonic acid in human monocyte-derived macrophages exposed to the inflammatory stimuli bacterial lipopolysaccharide (LPS) and opsonized zymosan (OpZ). Since PAF is derived from 1-alkyl-2-acyl-glycerophosphocholine, it was of interest to determine if this phospholipid precursor could also serve as a source of arachidonic acid. The day-5 macrophages incorporated 38% of the available [3H]arachidonic acid into lipid by 4 h, 54% of which was in phospholipid [phosphatidylcholine (PC) greater than phosphatidylethanolamine (PE) greater than phosphatidylinositol (PI)]. The proportion of label incorporated into ether-linked PC and PE increased with time. After prelabelling with [3H]arachidonic acid, the effect of stimuli on the redistribution of label within phospholipids was followed. Without stimulus there was a loss of label from PC, PI and phosphatidic acid by 3 h, but an increase of label in PE. The [3H]arachidonic acid that was lost from PC in the absence of stimulus was derived solely from the 1-acyl-linked species of PC, whereas an increase in label occurred in the 1-alkyl-linked species of PC. By contrast, LPS stimulation resulted in a preferential, dose-dependent loss of label from PC and PI, which was maximal between 1 and 3 h after adding the LPS. In addition, LPS induced a 35% decrease in the molar quantity of PI in the macrophages but had no effect on the quantity of PC, PE or phosphatidylserine. Stimulation with OpZ also resulted in a loss of label, mainly from PC and PI. Of the total label lost from PC in response to LPS or OpZ, approx. 50% was derived from the 1-alkyl-linked species. The results suggest that phospholipase C- and phospholipase A2-mediated mechanisms for arachidonic acid release are activated in human macrophages exposed to the inflammatory stimuli LPS and OpZ. In addition, 1-alkyl-linked PC can serve as a source of arachidonic acid and as a precursor for PAF production in the stimulated macrophages.

Arachidonic Acid↗
PubMed1996

Translocation of annexin I to plasma membranes and phagosomes in human neutrophils upon stimulation with opsonized zymosan: possible role in phagosome function.

Annexin I in the cytosol of resting neutrophils was translocated to the plasma membranes upon addition of opsonized zymosan (OZ). Maximum translocation could be detected 1 min after stimulation with OZ, and decreased thereafter. Subcellular fractionation studies demonstrated that annexin I could not be detected in the granule fractions in either resting or activated cells, but was found in association with the phagosome fraction. The marked translocation of annexin I was unique to OZ, since formyl-Met-Leu-Phe induced only slight translocation of annexin I to the plasma membranes, and phorbol 12-myristate 13-acetate had no effect at all. The mechanism regulating the translocation of annexin I is not clear. Annexin I is not phosphorylated in resting or stimulated cells. The correlation between the elevation in the intracellular calcium ion concentration ([Ca2+]i) and the degree of translocation of annexin I to the plasma membranes induced by the different stimuli, together with the inhibition of these processes by the addition of EGTA, indicate that the translocation of annexin I can probably be attributed to the rise in [Ca2+]i. However, this cannot be the sole mechanism since ionomycin, which caused an increase in [CA2+]i similar to that induced by OZ, was less efficient than OZ in inducing translocation of annexin I. The induction of annexin I translocation to the plasma membrane by OZ, which was the only agent that induced phagosome formation, and the detection of annexin I in the phagosome fraction, suggest that annexin I participates in phagosome function.

Annexin A1↗
PubMed1997

Cytosolic phospholipase A2 and its mode of activation in human neutrophils by opsonized zymosan. Correlation between 42/44 kDa mitogen-activated protein kinase, cytosolic phospholipase A2 and NADPH oxidase.

The role of cytosolic phospholipase A2 (cPLA2) and its mode of activation by opsonized zymosan (OZ) was studied in human neutrophils in comparison with activation by PMA. The activation of cPLA2 by 1 mg/ml OZ or 50 ng/ml PMA is evidenced by its translocation to the membrane fractions on stimulation. This translocation is consistent with dithiothreitol (DTT)-resistant phospholipase A2 (PLA2) activity detected in the membranes of activated cells. Neutrophils stimulated by either OZ or PMA exhibited an immediate stimulation of extracellular-signal-regulated kinases (ERKs). The inhibition of ERKs, DTT-resistant PLA2 and NADPH oxidase activities by the MAP kinase kinase inhibitor PD-98059 indicates that ERKs mediate the activation of cPLA2 and NADPH oxidase stimulated by either OZ or PMA. The protein kinase C (PKC) inhibitor GF-109203X inhibited epidermal growth factor receptor peptide kinase activity, the release of [3H]arachidonic acid, DTT-resistant PLA2 activity and superoxide generation induced by PMA, but did not inhibit any of these activities induced by OZ. PKC activity was similarly inhibited by GF-109203X in membrane fractions separated from neutrophils stimulated by either PMA or OZ. In the presence of the tyrosine kinase inhibit orgenistein, ERKs, PLA2 and NADPH oxidase activities were inhibited in cells stimulated by OZ, whereas they were hardly affected in cells stimulated by PMA. The results suggest that the activation of cPLA2 by PMA or OZ is mediated by ERKs. Whereas PMA stimulates ERKs activity through a PKC-dependent pathway, signal transduction stimulated by OZ involves tyrosine kinase activity leading to activation of ERKs via a PKC-independent pathway.

Calcium-Calmodulin-Dependent Protein Kinases↗