Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated some steps in the signal transduction pathway leading to the proliferation of synovial cells. 12-o-tetradecanoyl phorbol-13-acetate (TPA) which is known to stimulate phospholipid- and Ca(2+)-dependent protein kinase (C-kinase) enhanced the proliferation of synovial cells. The proliferation of synovial cells induced by interleukin-1 beta. Tumour necrosis factor alpha and granulocytes/macrophages colony stimulating factor, was inhibited by a potent C-kinase inhibitor, H7. These findings strongly suggested that the signal transduction pathway leading to proliferation of synovial cells is transmitted via C-kinase activation. Prostaglandin E2, which is known to stimulate adenylate cyclase, leading to the elevation of intracellular c-AMP level, inhibited the proliferation of synovial cells. This effect could also be mimicked by the addition of a cell permeable c-AMP analog, dibutyryl c-AMP or theophylline. Studies suggest that the feedback signal for proliferation of synovial cells was transmitted through c-AMP. We therefore conclude that signals for stimulation and inhibition of synovial cell proliferation are transmitted through different pathways.
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PMID:Intracellular signal transduction in proliferation of synovial cells. 131 50

1. Expression of cell adhesion molecules (CAM) on the lung microvascular endothelium is believed to play a key role in the recruitment of leukocytes in pulmonary inflammation. Moreover, regulation of CAM expression may be an important mechanism through which this inflammation may be controlled. Experimental evidence has suggested that combined phosphodiesterase (PDE) 3 and 4 inhibitors increase cyclic AMP levels within cells greater than inhibition of either isoenzyme alone. In the present study we assessed the effect of combinations of rolipram (PDE4 inhibitor), ORG 9935 (PDE3 inhibitor) and salbutamol (beta-agonist) on CAM expression and neutrophil or eosinophil adhesion to human lung microvascular endothelial cells (HLMVEC). 2. Tumour necrosis factor-alpha (TNF-alpha)-induced intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and E-selectin expression were measured on HLMVEC monolayers at 6 h by a specific ELISA technique in the presence of different combinations of medium, rolipram, ORG 9935 and salbutamol. 3. Rolipram in combination with salbutamol, but neither agent alone, inhibited TNF-alpha-induced E-selectin expression, whilst ICAM-1 and VCAM-1 expression were not affected. ORG 9935 had no significant effect on CAM expression alone. However, in combination with rolipram a syngergistic inhibition of VCAM-1 and E-selectin, but not ICAM-1, expression was observed. No further inhibition was seen in the additional presence of salbutamol. 4. Neutrophil adhesion to TNF-alpha-stimulated (6 h) HLMVEC was mainly E-selectin dependent in this model, as ENA2 an anti-E-selectin monoclonal antibody (mAb) abrogated neutrophil adhesion. Eosinophil adhesion was E-selectin-, ICAM-1- and VCAM-1-dependent, as assessed by the inhibitory activity of ENA2 and the ability of a mAb to the ICAM-1 ligand, CD18, and a mAb to the VCAM-1 ligand, VLA4, to attenuate adhesion. 5. Rolipram in the presence of salbutamol or ORG 9935 significantly inhibited neutrophil adherence to TNF-alpha-stimulated HLMVEC. Eosinophil adherence to monolayers was inhibited only when HLMVEC were activated in the presence of rolipram and ORG 9935. 6. Collectively, the findings presented in this manuscript suggest that inhibition of PDE4 with appropriate activation of adenylate cyclase is sufficient to inhibit induction of E-selectin expression on HLMVEC to a level that has functional consequences for neutrophil adhesion. In contrast, combined inhibition of PDE3 and 4 isoenzymes is necessary to inhibit VCAM-1 and to have inhibitory effects on eosinophil adhesion to activated HLMVEC. Upregulation of ICAM-1 expression on HLMVEC does not appear to be modulated by PDE3 and 4 inhibition. These data may have implications for the use of selective PDE4 inhibitors in lung inflammation.
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PMID:Modulation of cell adhesion molecule expression and function on human lung microvascular endothelial cells by inhibition of phosphodiesterases 3 and 4. 963 Mar 64

ABSTRACT The synthesis of the vasoconstrictor peptide endothelin-2 (ET-2) is dependent on hydrolysis of the biologically inactive intermediate big ET-2 by an endothelin-converting enzyme (ECE). Here, mechanisms inducing ET-2 synthesis have been investigated using the human renal adenocarcinoma cell line (ACHN). Synthesis of ET-2 by ACHN cells was inhibited by phosphoramidon (IC(50( congruent with11 microM). To determine whether ET-2 synthesis occurs in parallel with the metallopeptidase ECE-1, a putative processing peptidase for big ET-2, changes in the levels of their mRNAs were compared by semi-quantitative RT-PCR under conditions causing the upregulation of ET-2 synthesis. Tumour necrosis factor-alpha (TNFalpha), forskolin and a cell-permeable cAMP analogue (dibutyryl cAMP) caused concentration-dependent increases in ET-2 synthesis. Combination of forskolin or dibutyryl cAMP with TNFalpha produced a significantly greater increase in ET-2 production than these agents alone, indicating that adenylate cyclase and TNFalpha induce ET-2 synthesis by separate signalling pathways. Studies using receptor selective TNFalpha mutants, (125(I-TNFalpha binding and TNF receptor mRNA showed that type-1 TNF receptors mediate the ET-2 response to TNFalpha. PreproET-2 mRNA levels were increased by TNFalpha at 1 h and 2 h, but returned to control levels at 4 h. Treatment with forskolin significantly increased preproET-2 mRNA levels after 1 h and 4 h. ACHN cells expressed ECE-1b and ECE-1c, but not the ECE-1a isoform of this peptidase. RT-PCR for the combined isoforms ECE-1b/c/d showed TNFalpha to increase mRNA levels at 2 h and 4 h. Forskolin had no effect on ECE-1b/c/d mRNA levels. Thus, expression of ET-2 and ECE-1b/c/d mRNAs in ACHN cells do not display the co-ordinated regulation observed with typical peptide prohormone processing enzymes and their substrates.
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PMID:Endothelin-2 synthesis is stimulated by the type-1 tumour necrosis factor receptor and cAMP: comparison with endothelin-converting enzyme-1 expression. 1075 28