Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Isolated islets from adult rats or obese hyperglycemic (ob/ob) mice were incubated with human recombinant interleukin 1 beta in order to study whether the acute effects of the cytokine on islet insulin release are associated with changes in islet phospholipase C activity, Ca2+ handling or protein phosphorylation. The cytokine stimulated insulin release both at low and high glucose concentrations during one hour incubations. In short-term incubations (less than 1 min) interleukin 1 beta did not affect the production of inositoltrisphosphate. Addition of interleukin 1 beta affected neither the cytoplasmic free Ca2+ concentration at rest nor that observed subsequent to stimulation with a high concentration of glucose. Furthermore, the endogenous protein kinase C activity, as visualized by immunoprecipitation of a 32P-labelled substrate for this enzyme, was not altered by interleukin 1 beta. Separation of 32P-labelled proteins by means of 2-dimensional gel electrophoresis failed to reveal any specific effects of the cytokine on the total protein phosphorylation activity. These results suggest that the stimulatory effects on insulin release exerted by interleukin 1 beta are not caused by acute activation of phospholipase C and protein kinase C or by an alteration of islet Ca2+ handling of the B-cells.
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PMID:Human interleukin 1 beta stimulates islet insulin release by a mechanism not dependent on changes in phospholipase C and protein kinase C activities or Ca2+ handling. 268 30

In cultured vascular smooth muscle cells (VSMC), inflammatory cytokines such as interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha stimulated nitric oxide (NO) production via the expression of an inducible type of NO synthase (iNOS). A potent vasoconstrictor, angiotensin II (Ang II), which causes a rapid phospholipase C-mediated phosphoinositide hydrolysis via the Ang II type 1 (AT1) receptor in VSMC, by itself did not stimulate the production of nitrite, a stable metabolite of NO, but dose dependently inhibited the IL-1 beta-induced nitrite production. This inhibitory effect of Ang II was blocked by an AT1 receptor antagonist, CV-11974, but not by an Ang II type 2 receptor antagonist, PD 123319. The presence of Ang II during the early induction phase of iNOS was required for this inhibition. Consistently, Ang II suppressed IL-1 beta-induced increases in iNOS mRNA and protein levels. Ang II also inhibited increases in nitrite production and iNOS mRNA and protein levels caused by tumor necrosis factor alpha. A protein kinase C-activating phorbol ester, phorbol 12-myristate 13-acetate, and a membrane-permeable diacylglycerol, 1,2-dioctanoyl-glycerol, similarly inhibited the IL-1 beta-induced nitrite production and iNOS mRNA and protein expression, although repetitive additions were needed in the case of diacylglycerol. These results indicate that Ang II negatively modulates cytokine-induced NO production by blocking iNOS expression via the AT1 receptor in VSMC and suggest that protein kinase C could be involved in this process.
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PMID:Angiotensin II inhibits cytokine-stimulated inducible nitric oxide synthase expression in vascular smooth muscle cells. 751 70

We have previously shown that activation of the phosphatidyl-inositol/phospholipase C pathway could induce interleukin 6 (IL-6) release from U373MG human astrocytomes cells. We also found that, although interleukin 1 beta (IL-1 beta) did not activate phosphatidy-linositol turnover, it induced, a robust release of IL-6. In the present study, we examined the role of adenylate cyclase/cyclic 3',5'-adenosine monophosphate (cAMP) pathway in IL-6 release. Agents which mimicked (dibutyryl cAMP) or stimulated (isoproterenol and forskolin) cAMP formation were found to induce IL-6 release and their effects could be potentiated by 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor. On the other hand, in spite of its robust action on IL-6 release, IL-1 beta did not stimulate cAMP formation. Other possible signal transduction mechanisms involved in IL-1 beta-induced IL-6 release are discussed.
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PMID:cAMP is not involved in interleukin-1-induced interleukin-6 release from human astrocytoma cells. 752 12

Primary cultures of luteal cells have been used to determine both acute and chronic effects of cytokines on luteal cell function and viability. Gonadotrophin-stimulated progesterone production is inhibited by interleukin 1 beta (IL-1 beta), tumour necrosis factor alpha (TNF-alpha), or gamma-interferon (IFN-gamma), the last two cytokine being more effective than IL-1. In contrast, all three cytokines are potent stimulators of prostaglandin production by these cells. The mechanism by which prostaglandin synthesis is enhanced may differ slightly for each cytokine. In luteal cells, TNF-alpha appears to act primarily through stimulation of phospholipase A2, whereas IL-1 beta may activate phospholipase C and prostaglandin endoperoxide synthase (PGS) in addition to phospholipase A2. The mechanism of action of IFN-gamma has not yet been determined. In addition to the observed functional effects, cytokines may also promote cell death during luteal regression. Although the three cytokines mentioned have little or no effect on viability of cultured luteal cells when administered separately, combined treatment with TNF-alpha and IFN-gamma results in a substantial decrease in the number of viable cells. Inhibition of cytokine-stimulated prostaglandin production does not alter the cytotoxic effect of these cytokines. Expression of major histocompatibility (MHC) class I molecules on luteal cells is enhanced, and MHC class II molecules are induced, by exposure to IFN-gamma. This is especially intriguing, as MHC class II expression increases before luteal regression in vivo, and is suppressed in early pregnancy. In summary, evidence is rapidly accumulating that supports the hypothesis that the function or structural integrity of luteal cells may be modulated by resident immune cells. Future research will probably address how these local events are hormonally controlled, and if they can be modified to regulate corpus luteum function.
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PMID:Involvement of immune cells in regulation of ovarian function. 762 27

VCAM-1 is an immunoglobulin superfamily member that mediates adhesion of a variety of leukocytes to endothelial cells. VCAM expression has been associated with a variety of disease states and has been implicated in a number of normal processes. The predominant form of VCAM produced in human endothelial cells is a transmembrane protein containing seven immunoglobulin domains. In this study the murine VCAM gene has been characterized to allow the function(s) of VCAM to be studied in a small genetically accessible animal. While expression of an mRNA encoding a seven-immunoglobulin-domain transmembrane VCAM protein was seen in most tissues, the predominant change in VCAM expression upon interleukin 1 beta treatment was the induction of an alternatively spliced VCAM mRNA containing only the first three immunoglobulin domains. This message encodes a glycosylphosphatidylinositol (GPI)-anchored form of VCAM, VCAMGPI. VCAMGPI was efficiently cleaved from the cell surface by phosphatidylinositol-specific phospholipase C, mediated adhesion to leukocytes in a very late antigen 4-dependent manner, and was produced by mouse endothelial cell lines in culture. These data demonstrate that alternate forms of VCAM are produced under different physiological conditions and suggest that VCAMGPI may have a distinct role in inflammatory processes.
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PMID:Cytokine induction of an alternatively spliced murine vascular cell adhesion molecule (VCAM) mRNA encoding a glycosylphosphatidylinositol-anchored VCAM protein. 768 58

Tumor necrosis factor alpha (TNF alpha), interleukin 1 beta (IL-1 beta), and endotoxin (LPS) are potent pro-inflammatory mediators which induce multiple and diverse biological responses in a wide variety of cell types. However, these pro-inflammatory mediators also have significant overlap and redundancy in their biological effects. This suggests that there is significant diversity in second messenger signal transduction systems induced by these stimuli to explain the diversity in biological responses, as well as significant redundancy. Here we show that one such second messenger common to several proinflammatory stimuli may be phosphatidic acid (PA). Intracellular PA species, which may have intracellular signaling functions, are rapidly induced in P388 monocytic leukemia cells by TNF alpha, IL-1 beta, or LPS. These PA species vary according to the bond type (i.e., sn-1 ester vs. ether vs. vinyl ether), acyl chain length, and the degree of saturation in the sn-1 and sn-2 positions. Although PA itself may have direct second messenger activities, many of the PA species induced are converted to diacylglycerol species (DG), which are structurally distinct from the DGs generated by phosphatidylcholine-specific phospholipase C (PC-PLC). Lisofylline [(R)-1-(5-hydroxyhexyl)-3,7-dimethylxanthine; LSF] selectively inhibits generation of selected species of PA in P388 cells induced by TNF alpha, IL-1 beta or LPS. TNF alpha-induced sphingomyelin hydrolysis, PLC-mediated PC hydrolysis, and DG kinase-mediated PA formation or TNF alpha-induced NF-kappa B activation and apoptosis are not inhibited by LSF. LSF has a marked protective effect in a variety of acute inflammatory animal models that may be due to inhibition of this shared second messenger pathway involving PA.
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PMID:Potential role for phosphatidic acid in mediating the inflammatory responses to TNF alpha and IL-1 beta. 770 34

The human astroglioma cell D384 possesses adenosine A2B receptors coupled to the formation of cyclic AMP. These cells also possess bradykinin B2 receptors coupled to phospholipase C and consequent increases in intracellular calcium and protein kinase C. Interleukin 1 beta causes an increase in c-fos, AP-1 transcriptional activity and an increased expression of several genes including NGF, but the initial signalling events are unknown. Bradykinin causes a rapid decrease in A2B receptor mediated cAMP formation, via a mechanism that involves calcium, but not cGMP, and appears to depend upon a direct decrease in adenylyl cyclase. Il-1 beta causes a slowly developing (18-24 h) increase in A2B receptor signalling. The results indicate that adenosine effects in glial cells, believed to be important in neuroprotection, are modified in the short and long-term by inflammatory mediators.
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PMID:Adenosine A2B receptor signalling is altered by stimulation of bradykinin or interleukin receptors in astroglioma cells. 795 Sep 78