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Biomedical subjects

K Resch

Publications and source records attributed to K Resch.

At least 37 records · Page 2Linked to original sources
PubMed1991

Protein kinase C activation and protooncogene expression in differentiation/retrodifferentiation of human U-937 leukemia cells.

Human U-937 leukemia cells differentiate along the monocytic lineage following 3-day exposures to 12-O-tetradecanoylphorbol-13-acetate (TPA). This induction of differentiation is accompanied by adherence and loss of proliferation, as well as expression/repression of differentiation-associated genes. Long term culture of TPA-differentiated U-937 cells in the absence of phorbol ester for 32-36 days resulted in a process of retrodifferentiation. The retrodifferentiated cells detached from the substrate and reinitiated proliferation. Other cellular parameters, such as glycosidase activities, cytokine release, and filament expression, returned to levels similar to that observed in uninduced cells. Treatment of U-937 cells with TPA resulted in a rapid translocation of protein kinase C (PKC) from the cytosol to cell membrane fractions within 2-8 min. Increased levels of membrane-associated PKC activity persisted until 17-29 days. However, longer periods of incubation were associated with a return to the distribution of PKC in control cells. Activation of PKC has been implicated in the regulation of certain immediate early response genes, and in the present studies, TPA rapidly induced c-fos and c-jun gene expression. Levels of c-fos and c-jun transcripts remained elevated during periods of PKC activation and also returned to levels observed in control cells by 30-36 days, when the cells entered retrodifferentiation. Staurosporine, a nonspecific inhibitor of PKC, partially blocked TPA-induced adherence and growth inhibition and concomitantly prevented TPA-induced c-fos and c-jun gene expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaloids↗
PubMed1990

Glucocorticoid-induced reduction of prostanoid synthesis in TPA-differentiated U937 cells is mainly due to a reduced cyclooxygenase activity.

The molecular mechanism of the glucocorticoid-induced inhibition of prostanoid synthesis was investigated in human monoblastoid U937 tumor cells and phorbol ester (TPA)-differentiated U937 cells. Prostanoid synthesis was inhibited in TPA-differentiated U937 cells by glucocorticoids such as dexamethasone and prednisolone, whereas aldosterone and progesterone showed no inhibitory effect. None of these methods had any influence on prostanoid secretion of undifferentiated U937 cells. Receptor binding studies revealed the presence of glucocorticoid receptors in both undifferentiated and TPA-differentiated U937 cells (Kp approximately 5 x 10(-9)M), however, the number of receptors per cell was increased 10-fold in TPA-differentiated U937 cells. Expression of lipocortin I and II as measured by Western blot analysis was not affected by dexamethasone. In TPA-differentiated cells, dexamethasone decreased the activities of two enzymes essential for prostanoid synthesis, cyclooxygenase and phospholipase A2, by 60-70% and 30%, respectively. Cells pretreated with the translation inhibitor cyclohexmide and dexamethasone showed similar cyclooxygenase and phospholipase A2 activities as cells treated with cycloheximide alone. Western blot analysis demonstrated that the significantly decreased cyclooxygenase activity correlated with an inhibited protein synthesis. In this human macrophage-like model glucocorticoids thus interfere at least at two levels with prostanoid synthesis by inhibiting the activities of phospholipase A2 as well as cyclooxygenase.

Cell Line↗
PubMed1990

The ratio of macrophage prostaglandin and leukotriene synthesis is determined by the intracellular free calcium level.

The induction of eicosanoid synthesis in various cell types by different physiological stimuli is dependent on an increase in the intracellular calcium level and stimulation of the protein kinase C (PKC). In a model system this can be mimicked by using calcium ionophores and direct PKC activators. In mouse peritoneal macrophages calcium ionophores induced the formation of prostaglandin E2 (PGE2) and leukotriene C4 (LTC4). A synergistic enhancement of both eicosanoids could be achieved by simultaneous addition of the calcium ionophore A23187 together with a suboptimal dose of the direct protein kinase C activator 12-O-tetradecanoylphorbol 13-acetate (TPA). Low concentrations of the ionophore, resulting in only marginally increased intracellular calcium levels, led to a more than additive prostaglandin E2 production in combination with TPA. Higher concentrations of A23187 together with TPA favoured LTC4 synthesis, whereas PGE2 levels at the same time were even diminished. This observed shift from prostaglandin to leukotriene formation was amplified by simultaneous addition of indomethacin. Manganese as inhibitor of the A23187-induced calcium influx decreased PGE2 synthesis. On the other hand, in the presence of manganese LTC4 production was also inhibited at high concentrations of A23187 but elevated in the absence or at low doses of A23187. Our data provide evidence that in macrophages the ratio of cyclooxygenase and lipoxygenase products caused by mediators, acting via the phospholipase C or D/PKC signal transduction pathway, is regulated by the extent of the intracellular calcium increase.

Animals↗
PubMed1990

Altered arachidonic acid metabolism during differentiation of the human monoblastoid cell line U937.

The human cell line U937 was used as a model for differentiation along the mononuclear phagocyte lineage. Following treatment with the phorbol ester TPA, PGE2 and TxB2 secretion was induced 50-100-fold, and both PGF2 alpha and PGI2 levels became detectable in the supernatant of TPA-differentiated U937 cells. The content of the prostaglandin precursor, arachidonic acid, remained unchanged in the cellular phospholipids of undifferentiated and TPA-differentiated U937 cells. Of the enzymes involved in the availability and metabolism of arachidonic acid, phospholipase A2 activity was increased 2-fold in the membranes of TPA-differentiated U937 cells, whereas lysophosphatide acyltransferase activity remained unaltered. Cyclooxygenase activity, however, was enhanced 5-10-fold, which was due to enhanced expression of the enzyme as demonstrated by dot-blot analysis. The data suggest that the capacity to secrete prostaglandins is acquired during differentiation with TPA and results mainly from an increased cyclooxygenase activity. Despite the capacity of TPA-differentiated U937 cells to synthesize prostaglandins, none of the known monocytic stimuli further stimulated prostaglandin secretion in TPA-differentiated U937 cells. Generation of leukotrienes appears to represent a later state in the differentiation along the monocyte-macrophage lineage, since neither LTB4 nor cysteinyl-leukotrienes were detectable in the supernatants of either undifferentiated or TPA-differentiated U937 cells.

Arachidonic Acid↗
PubMed1990

Alterations in glycosylation and lectin pattern during phorbol ester-induced differentiation of U937 cells.

Incubation of the human monoblastoid tumor cell line U937 with 5 x 10(-9) M 12-O-tetradecanoylphorbol-13-acetate (TPA) for 3 days was associated with marked morphological and functional changes including adherence of the cells and cessation of proliferation. While growth arrest and the viability of the cells were not influenced, the TPA-induced adherence of U937 cells could be totally blocked by incubation with tunicamycin, suggesting an involvement of N-linked carbohydrates in these cell attachment processes. The isolation and characterization of endogenous lectins with specificities for lactose, L-fucose, and D-mannose from U937 controls and TPA-differentiated U937 cells demonstrated marked differences in either the pattern and the distribution of these sugar-specific carbohydrate-binding proteins. Our results indicate that alterations in cell-surface carbohydrates are of central importance for the attachment of the differentiating U937 tumor cells.

Cell Adhesion↗
PubMed1990

The G protein coupling T cell antigen receptor/CD3-complex and phospholipase C in the human T cell lymphoma Jurkat is not a target for cholera toxin.

Intact Jurkat cells could be stimulated by monoclonal antibodies against the Tcell antigen receptor complex (OKT3 directed against the CD3 complex, BMA031 directed against constant framework epitopes in the alpha/beta heterodimer). The accumulation of inositol phosphates was inhibited by prior incubation of the cells with cholera holotoxin. The inhibitory effect of cholera toxin (CT) was not cAMP mediated because forskolin (a direct activator of adenylate cyclase) did not mimic the inhibitory effect. When measuring phospholipase C (PLC) in a cell-free assay system by using [3H]inositol-labeled membranes, the enzyme could be stimulated by the poorly hydrolyzable GTP analogue guanosine 5'-O-(thiotriphosphate (GTP gamma S). Both anti-receptor antibodies augmented the GTP gamma S stimulatory effect, while the antibodies alone had no stimulatory capacity. In membranes from CT-pretreated cells, whereas the antibodies lost their stimulatory effect on PLC as in untreated cells, whereas the antibodies lost their stimulatory capacity in the presence of GTP gamma S. These data imply that CT exerts its inhibitory effect on signaling by acting at the receptor level while the PLC regulating G protein is not a target for CT-mediated alterations. This assumption is supported by the finding that in intact Jurkat cells CT, which ADP ribosylated only the alpha-subunit of the stimulatory G protein of the adenylate cyclase, led to a loss of the T cell antigen receptor complex from the cell surface as demonstrated by a decrease of receptor density using flow cytometry analysis. Receptor loss could not be achieved by forskolin treatment or incubation of the cells with the binding subunit of the toxin alone.

Adenosine Diphosphate Ribose↗
PubMed1990

Activation signals in human lymphocytes: interleukin 2 synthesis and expression of high affinity interleukin 2 receptors require differential signalling for the activation of protein kinase C.

The mitogenic activation of resting T lymphocytes involves two distinct cellular events, the synthesis of the ultimate mitogen interleukin 2 and the synthesis and expression of receptors for it. In order to get more detailed information on the mechanisms associated with these activating steps (the effects of different stimuli, leading to activation of protein kinase C were investigated in human lymphocytes). The anti-T-cell receptor (TCR) and anti-CD3 monoclonal antibodies (BMA 031 and BMA 030, respectively), as well as the combination of the phorbol ester, TPA, with a calcium ionophore-induced interleukin 2 synthesis and subsequent proliferation in human peripheral blood lymphocytes. Incubation of cells with synthetic diacylglycerols and calcium ionophores proved to be effective in expression of high affinity interleukin receptors, no detectable amounts of interleukin 2 were, however, synthetized. When diacylglycerols were, however, added repetitively, interleukin 2 was also produced. Both anti-TCR/CD3 antibodies and TPA or DiC8 caused activation and translocation of protein kinase C from the cytosol to the plasma membrane. Significant differences, however, were observed between the time kinetics of the translocation of the enzyme. In plasma membranes of TPA-stimulated cells activation of protein kinase C was detectable up to 4 hr. In contrast, the highest specific activity of protein kinase C was measured in the plasma membranes after 15 min of DiC8 addition to cells. Anti-CD3 monoclonal antibodies activated protein kinase C in a biphasic manner. Shortly after binding of BMA 030 to the T cell antigen receptor/CD3 complex the activity of protein kinase C was increased in the plasma membrane, then it declined to control levels followed by a second long-lasting activation of the enzyme up to 4 hr. These results suggest different signal requirements for different activation steps. While for synthesis and expression of interleukin 2 receptors a short term activation of protein kinase C is sufficient, long-term activation of the enzyme is necessary for interleukin 2 synthesis in human lymphocytes.

Biological Transport↗
PubMed1990

Pertussis toxin B-subunit-induced Ca2(+)-fluxes in Jurkat human lymphoma cells: the action of long-term pre-treatment with cholera and pertussis holotoxins.

The exotoxins of Bordetella pertussis and Vibrio cholera have been used to investigate signal transduction in the human T-cell lymphoma Jurkat. Stimulation of the cells, leading to an increase in cytoplasmic free calcium, could be achieved by the anti-T-cell receptor complex antibody OKT3 and by pertussis holotoxin (PTHT), or its B-subunit (PTB), but not by cholera holotoxin (CTHT) or its B-subunit (CTB). Both holotoxins ADP-ribosylated specifically G-proteins in the plasma membrane of intact cells, while their B-subunits had no ADP-ribosyltransferase activity. Incubation of the cells with CTHT led to a state of unresponsiveness to all stimulants. CTB was without any effect, indicating that the ADP-ribosyltransferase activity of cholera toxin (located in the A-subunit of the holotoxin) was necessary for the inhibition of cellular signalling. The inhibitory effect of cholera toxin on the pertussis toxin action was not due to a blockade of pertussis toxin interaction with the cell surface, because pertussis toxin was still able to ADP-ribosylate membrane proteins in cholera toxin treated intact cells. In addition, the cholera toxin mediated inhibition was not due to elevated levels of cyclic-AMP, as forskolin (a direct activator of the adenylate cyclase) and no inhibitory effect. The stimulating effect of PTHT was independent of its ADP-ribosyltransferase activity, because it could also be obtained by the B-subunit alone. In addition, the increase of cytoplasmic free calcium after stimulation by PTHT clearly preceded the ADP-ribosylation. Pre-treatment with PTHT, PTB or OKT3, led to a long lasting increase in the level of intracellular Ca2+ in Jurkat cells, which could not, therefore, be stimulated further. Inhibition by cholera holotoxin of the stimulation by OKT3 and pertussis toxin (PTHT and PTB) imply that the mitogenic effect of pertussis toxin is perhaps mediated via the T-cell antigen receptor signalling cascade. The presented data do not support the idea that a pertussis toxin-sensitive G-protein is involved in coupling the T-cell antigen receptor to the phospholipase C.

Adenosine Diphosphate Ribose↗
PubMed1990

Interleukin 1-alpha and tumor necrosis factor-alpha induce oxygen radical production in mesangial cells.

Adherent human mesangial cells (HMC) were unable to phagocytose serum-treated zymosan (STZ), nevertheless this stimulus (1 mg/ml) induced a marked immediate increase of H2O2 and O2- release at a rate of 3.15 +/- 0.35 and 3.40 +/- 0.12 nmol/10(6) HMC/hr, respectively. Zymosan alone resulted in no release of either H2O2 or O2-. Phorbol myristate acetate (PMA, 2 X 10(-6) M) had only marginal effects on HMC leading to the generation of 0.273 +/- 0.014 nmol O2-/10(6) HMC/hr. After a lag period, human recombinant tumor necrosis factor-alpha (TNF-alpha) and human recombinant interleukin 1-alpha IL-1 alpha) both induced significant O2- production measured as SOD inhibitable reduction of cytochrome c, 5 X 10(-5) M, by adherent HMC for up to five hours, the maximum rates being 3.04 +/- 0.08 and 3.2 +/- 0.08 nmol/10(6) HMC/hr for IL-1 alpha and TNF-alpha, respectively. Significant O2- release was detectable at 0.625 ng/ml (37 pM) IL-1 alpha or 1 ng/ml (59 pM) TNF-alpha (P less than 0.05). Catalase inhibitable H2O2 production was also induced by IL-1 alpha and TNF-alpha in a dose dependent manner. Using scopoletin (40 nM) and 1 microM peroxidase we fluorimetrically measured 1.73 +/- 0.14 and 1.49 +/- 0.19 nmol H2O2/10(6) HMC/hr induced by IL-1 alpha (25 ng/ml) and TNF-alpha (20 ng/ml). Finally, we ascertained the type of radical species produced by HMC stimulated by cytokines employing ESR-spin-trapping with DMPO.2+ These results demonstrated that O2- was the primary radical species formed.(ABSTRACT TRUNCATED AT 250 WORDS)

Glomerular Mesangium↗
PubMed1990

Monokines and platelet-derived growth factor modulate prostanoid production in growth arrested, human mesangial cells.

Previous studies have demonstrated considerable prostanoid production by cultured proliferating rat mesangial cells (MC). In this study, human mesangial cells (HMC) were examined during serum-free culture in which the cells were reversibly growth arrested and did not suffer obvious irreversible functional changes. Non-stimulated cells released 2 to 10 pg/24 hr/micrograms cellular protein of PGE2, PGF2 alpha, 6-keto-PGF1 alpha, while TXB2 was not detectable. Stimulation with interleukin-1 beta (IL-1 beta) or tumor necrosis factor alpha (TNF alpha) induced up to 18-fold (IL-1 beta) or up to fourfold (TNF alpha) increases of prostanoid release. Combinations of the two monokines resulted in significant synergistic induction of PGE2 and 6-keto-PGF1 alpha up to 38 times that of control cells. Interleukin-6 (IL-6) and the HMC-mitogen, platelet-derived growth factor-BB (PDGF-BB) only induced marginal increases in HMC prostanoid generation. However, when PDGF-BB or -AB was combined with IL-1 beta or IL-6, prostanoid generation by HMC was synergistically increased up to 222-fold (IL-1 beta) or 12-fold (IL-6) above the control values, with the induction of PGE2 greater than 6-keto-PGF1 alpha greater than PGF2 alpha much greater than TXB2. In the case of IL-1 beta + PDGF-BB the induction of PGE2 release was at least partly due to the synergistic induction of cyclooxygenase activity. These findings demonstrate that both proliferating and reversibly growth arrested HMCs release prostaglandins in response to various inflammatory stimulators and combinations thereof. The findings support the important role of HMC in the regulation of glomerular hemodynamics during inflammatory processes.

Cell Division↗
PubMed1990

Human fibroblasts release low amounts of reactive oxygen species in response to the potent phagocyte stimulants, serum-treated zymosan, N-formyl-methionyl-leucyl-phenylalanine, leukotriene B4 or 12-O-tetradecanoylphorbol 13-acetate.

Cell lines of human fibroblasts from primary cultures released reactive oxygen species, and displayed an increase in low-level chemiluminescence when stimulated with serum-treated zymosan, N-formyl-methionyl-leucyl-phenylalanine, leukotriene B4, or 12-O-tetradecanoylphorbol 13-acetate, all of which are known stimulants of respiratory burst in phagocytic cells. Non-serum-treated zymosan, interleukin-6, interleukin-2, interferon-gamma or complement factor C3b were ineffective. The primary radical species produced was O theta.2. Radical formation was continuous for up to 4 h, and it did not occur as an oxidative burst. The low level chemiluminescence probably arose from the excitation of carbonyl groups, since it remained unchanged in the presence of azide and 1,4-diazabicyclo[2.2.2]octane. While the release of reactive oxygen species in phagocytes has a function in defense mechanisms, the sustained production of such species in tissue cells may have a role in signaling mechanisms. The amounts of reactive oxygen species released by the fibroblasts upon stimulation with the stimulants mentioned above were low in comparison with the known stimulatory effects of cytokines [Meier et al. (1989) Biochem. J. 263, 539-545].

Electron Spin Resonance Spectroscopy↗
PubMed1990

Human fibroblasts release reactive oxygen species in response to treatment with synovial fluids from patients suffering from arthritis.

Human fibroblasts in primary culture released reactive oxygen species upon exposure to synovial fluid obtained by joint aspiration from twelve patients suffering from rheumatoid arthritis. The primary radical produced was O2- as determined by ESR spin trapping and cytochrome c reduction. In contrast to the oxidative burst in granulocytes and monocytes, radical formation proceeded continuously for at least four hours. Low-level chemiluminescence was increased upon exposure to inflammatory human synovial fluids. Spectral characteristics and effects of azide and 1,4-diazabicyclo-(2,2,2)-octane led to the conclusion that the photoemissive species were excited carbonyls. Radical production and light emission were not altered either by xanthine or allopurinol, nor by azide, cyanide or rotenone. The O2- production increased in the presence of NADH or NADPH, making an NAD(P)H oxidase a likely source. The liberation of reactive oxygen species correlated with the number of leukocytes present in the inflammatory joint fluids, but not with the concentrations of immunoglobulins and complement factor C3.

Arthritis, Rheumatoid↗
PubMed1990

Differentiation and retrodifferentiation of U937 cells: reversible induction and suppression of intermediate filament protein synthesis.

Significant morphological and functional changes were observed when human monoblastoid U937 tumor cells growing in suspension were induced by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) for 72 h to differentiate along the monocyte/macrophage pathway. These include adherence of the cells to each other and to the substratum, alterations in cell-surface antigen expression and cessation of autonomous proliferation. In this study, we show by both, hybridization analysis of RNA and immunoblotting that an enhanced expression of the intermediate filament (IF) subunit proteins vimentin, lamin A and lamin C accompanied the TPA-induced differentiation process. After long-term culture of differentiated U937 cells in the absence of TPA (more than 28 days), however, the adherent cells retracted their pseudopodia, detached and started again to proliferate. This "retrodifferentiation" process, not previously described was paralleled by a rapid down-regulation of both, IF mRNA and protein synthesis back to the level of undifferentiated U937 control cells. These data suggest a functional relationship between the expression of vimentin and lamins A and C and the differentiation process taking place in these cells.

Cell Differentiation↗
PubMed1989

Activation signals in human lymphocytes. Incorporation of polyunsaturated fatty acids into plasma membrane phospholipids regulates IL-2 synthesis via sustained activation of protein kinase C.

Human PBL activated with anti-TCR/CD3 mAb express high affinity receptors for IL-2, synthesize IL-2, and subsequently proliferate. In contrast, lymphocytes activated by dioctanoylglycerol (DiC8) and ionomycin express high affinity receptors; however, no IL-2 synthesis is detectable. Anti-TCR/CD3 antibodies, as well as DiC8 cause translocation of protein kinase C (PKC) from the cytosol to the plasma membrane. In DiC8-stimulated cells translocation of PKC is detectable after 15 min, then it declines to control levels. In lymphocytes activated by antiTCR/CD3 mAb translocation of PKC is detectable after 15 min, then it declines to control levels, followed by a second, long lasting activation of the enzyme up to 4 h. Addition of polyunsaturated fatty acids to DiC8 + ionomycin-treated cells leads to IL-2 synthesis and proliferation. Incorporation of poly-unsaturated fatty acids into plasma membrane phospholipids results in long term activation of PKC. The results suggest that elevated incorporation of polyunsaturated fatty acids and thus continuous activation and translocation of PKC represents a necessary early signal for IL-2 synthesis and proliferation in human lymphocytes.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1989

Human fibroblasts release reactive oxygen species in response to interleukin-1 or tumour necrosis factor-alpha.

Human fibroblasts in primary culture released reactive oxygen species upon stimulation with cytokines such as interleukin-1 alpha (IL-1) or tumour necrosis factor-alpha (TNF). The primary radical produced was O2.- as determined by e.s.r. spin trapping and cytochrome c reduction. In contrast to the oxidative burst in granulocytes and monocytes, radical formation took place continuously for at least 4 h. Low-level chemiluminescence was increased by stimulation with IL-1 and TNF. Spectral characteristics and tests with azide led to the conclusion that the photoemissive species were excited carbonyls and not singlet oxygen. Further, there was a liberation of ethane from the cells. Radical production and light emission were not altered by either xanthine or allopurinol, nor by azide, cyanide or rotenone. O2.- production increased in the presence of NADH or NADPH, making an NAD(P)H oxidase a likely source.

Cytochrome c Group↗
PubMed1989

Prostaglandin E2 production is synergistically increased in cultured human glomerular mesangial cells by combinations of IL-1 and tumor necrosis factor-alpha 1.

Both IL-1 alpha and IL-1 beta and TNF-alpha induced a time- and dose-dependent release of authentic PGE2 from cultured human glomerular mesangial cells (HMC). This release became significant only after a 4- to 6-h lag phase, and was abolished by inhibition of protein synthesis, and was not related to cell proliferation. Combinations of IL-1 and TNF-alpha when added simultaneously to HMC resulted in a dose-dependent synergistic increase in PGE2 production. These stimulatory effects were specifically inhibited by anticytokine antibodies and the synergistic effect required the simultaneous presence of both IL-1 and TNF-alpha. Arachidonic acid (AA) release experiments and measurement of cyclooxygenase activity, revealed that while both were increased by IL-1 beta and TNF-alpha alone (IL-1 beta greater than TNF-alpha), combinations of IL-1 beta and TNF-alpha resulted in only additive increases in AA release and cyclooxygenase activity. Taken together, these data suggest that stimulation of PGE2 in HMC, by combinations of these cytokines, is not rate limited by AA release or cyclooxygenase activation, but may be related to the induction of the distal enzymes controlling specific PG synthesis.

Adult↗
PubMed1989

Regulation of prostaglandin synthesis by protein kinase C in mouse peritoneal macrophages.

Resident mouse peritoneal macrophages synthesized and released prostaglandins (PGs) when challenged with 12-O-tetradecanoylphorbol 13-acetate (TPA) or 1,2-dioctanoyl-sn-glycerol (DiC8). Both stimuli were found to activate Ca2+/phospholipid-dependent protein kinase C (PKC). 1-(5-Isoquinolinesulphonyl)-2-methylpiperazine ('H-7') and D-sphingosine, known to inhibit PKC by different mechanisms, were able to decrease the PKC activity of macrophages in a dose-dependent manner. Addition of either PKC inhibitor decreased PG synthesis and also the release of arachidonic acid (AA) from phospholipids induced by TPA or DiC8. Simultaneously TPA or DiC8 also decreased incorporation of free AA into membrane phospholipids of macrophages. AA incorporation could be restored, however, by pretreatment with the PKC inhibitors. Our results demonstrate an involvement of PKC in the regulation of PG synthesis in mouse peritoneal macrophages and provide further evidence that reacylation of released fatty acids may be an important regulatory step.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗