Differential inhibition of human neutrophil functions

Wright, Clifford D.; Kuipers, Paul J.; Kobylarz-Singer, Dianne C.; Devall, Larry J.; Klinkefus, Beth A.; Weishaar, Ronald E.

doi:10.1016/0006-2952(90)90304-4

Cited by 92 publications

(7 citation statements)

References 44 publications

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“…Under these conditions, cell exposure to C5a may also produce excessive cAMP, which could interfere with activation of PLC, PKC, etc. (40,43,46). If cAMP levels were elevated, the MAPK response was also inhibited (47)(48)(49), which may represent an additional mechanism of C5a-induced neutrophil dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Complement-Induced Impairment of Innate Immunity During Sepsis

Huber‐Lang

Younkin

Sarma

et al. 2002

The Journal of Immunology

170

158

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This study defines the molecular basis for defects in innate immunity involving neutrophils during cecal ligation/puncture (CLP)-induced sepsis in rats. Blood neutrophils from CLP rats demonstrated defective phagocytosis and defective assembly of NADPH oxidase, the latter being due to the inability of p47phox to translocate from the cytosol to the cell membrane of neutrophils after cell stimulation by phorbol ester (PMA). The appearance of these defects was prevented by in vivo blockade of C5a in CLP rats. In vitro exposure of neutrophils to C5a led to reduced surface expression of C5aR and defective assembly of NADPH oxidase, as defined by failure in phosphorylation of p47phox and its translocation to the cell membrane, together with failure in phosphorylation of p42/p44 mitogen-activated protein kinases. These data identify a molecular basis for defective innate immunity involving neutrophils during sepsis.

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Section: Discussionmentioning

confidence: 99%

Complement-Induced Impairment of Innate Immunity During Sepsis

Huber‐Lang

Younkin

Sarma

et al. 2002

The Journal of Immunology

170

158

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“…Studies of several types of leukocytes, e.g. eosinophils (14), monocytes (15), and neutrophils (16), all highly active in generation of ROM, have shown that only PDE4 inhibitors suppress NADPH oxidase and ROM synthesis in these cell types (14 -16).…”

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confidence: 99%

Compartmentalization of cAMP Signaling in Mesangial Cells by Phosphodiesterase Isozymes PDE3 and PDE4 REGULATION OF SUPEROXIDATION AND MITOGENESIS

Chini¹,

Grande

Chini³

et al. 1997

Journal of Biological Chemistry

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Some major pathobiologic processes in renal mesangial cells, elicited in response to immunoinflammatory stimuli, are modulated via cAMP-protein kinase A (PKA) signaling pathways; namely, generation of reactive oxygen metabolites (ROM) and accelerated proliferation of mesangial cells. We investigated the role of cAMP phosphodiesterase (PDE) isozymes in these regulatory mechanisms. Generation of ROM in cultured rat mesangial cells was inhibited by selective inhibitors of PDE4, rolipram and denbufylline, whereas PDE3 inhibitors, cilostamide and lixazinone, had no effect. Conversely, cilostamide or lixazinone suppressed mitogenic synthesis of DNA in mesangial cells, but 1 M rolipram or 1 M denbufylline showed no inhibitory effect. The efficacy of PDE isozyme inhibitors (IC 50 ) to suppress [ 3 H]thymidine incorporation or ROM generation paralleled IC 50 values for inhibition of cAMP PDE. Incubation of mesangial cells with either rolipram alone or with cilostamide alone increased significantly in situ activity of PKA in mesangial cells, assessed by (؊cAMP/؉cAMP) PKA activity ratio, and the stimulatory effects were additive. Results indicate that in mesangial cells a cAMP pool that is metabolized by PDE4 activates PKA and thereby inhibits ROM generation; another cAMP pool that is metabolized by PDE3 activates another PKA (isozyme or pool) which suppresses proliferation of mesangial cells. We propose that in mesangial cells, a cAMP-PKA pathway that regulates mitogenesis is determined by activity of PDE3, whereas another cAMP-PKA pathway is directed by activity of PDE4 and controls ROM generation. Therefore, two PDE isozymes within one cell type compartmentalize distinct cAMP signaling pathways.Mesangial cells in kidney glomeruli are specialized pericytes (1) that are located in the intercapillary spaces of glomeruli and comprise about 30% of glomerular cells (2). Mesangial cells have some properties, such as contractility, reminiscent of smooth muscle cells, and some that are common to monocytes and macrophages, i.e. phagocytosis or the ability to generate reactive oxygen metabolites (ROM) 1 (3,4). According to the current view, mesangial cells have a key role in maintaining the integrity of renal glomerular structure and function mainly by regulating capillary blood flow, uptake of macromolecules by phagocytosis, and synthesis of the extracellular matrix (1,3,4). Pathobiologic responses of mesangial cells to immunoinflammatory stimuli often determine and/or contribute to pathogenic processes involved in the development of acute or chronic glomerulonephritides, in particular, mesangial proliferative glomerulonephritis (5, 6).In our recent studies of rat mesangial cells grown in primary culture we observed that inhibition of cyclic-3Ј,5Ј-nucleotide phosphodiesterase (PDE) isozyme type-3 (PDE3) by selective inhibitors causes activation of cAMP-protein kinase A (PKA) and suppresses mesangial cell proliferation, either basal or stimulated by addition of growth factors such as epidermal growth factor or platelet-derived g...

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“…Chemotactic stimuli have been shown to cause the selective release of the content of specific and gelatinase granules, while azurophil granules are retained unless cells are pretreated with cytochalasin B (9,10). We demonstrated that FMLP and calcium ionophore A23 187 induced the release of met-enkephalin-containing peptides without pretreatment with cytochalasin B.…”

Section: Resultsmentioning

confidence: 77%

Proenkephalin system in human polymorphonuclear cells. Production and release of a novel 1.0-kD peptide derived from synenkephalin.

Vindrola¹,

Padros²,

Sterin-Prync³

et al. 1990

J. Clin. Invest.

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In the hematopoietic system a pluripotent stem cell generates precursors for lymphoid and myeloid lineages. Proenkephalinderived peptides were previously detected in differentiated lymphoid cells. We have studied whether the proenkephalin system is expressed in a typical differentiated cell of the myeloid lineage, the neutrophil. Human peripheral polymorphonuclear cells contain and release proenkephalin-derived peptides. The opioid portion of proenkephalin (met-enkephalincontaining peptides) was incompletely processed, resulting in the absence of low molecular weight products. The nonopioid synenkephalin (proenkephalin 1-70) molecule was completely processed to a 1.0-kD peptide derived from the COOH-terminal. This molecule was characterized in neutrophils by biochemical and immunocytochemical methods. The chemotactic peptide FMLP and the calcium ionophore A23187 induced the release of the proenkephalin-derived peptides, and this effect was potentiated by cytochalasin B. The materials secreted were similar to those present in the cell, although in the supernatant a higher proportion corresponded to more processed products. The 1.0-kD peptide was detected in human, bovine, and rat neutrophils, but the chromatographic pattern of synenkephalin-derived peptides suggests a differential posttranslational processing among species. These findings demonstrate the existence of the proenkephalin system in human neutrophils and the production and release of a novel 1.0-kD peptide derived from the synenkephalin molecule. The presence of opioid peptides in neutrophils suggests their participation in the inflammatory process, including a local analgesic effect. (J.

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Differential inhibition of human neutrophil functions

Cited by 92 publications

References 44 publications

Complement-Induced Impairment of Innate Immunity During Sepsis

Complement-Induced Impairment of Innate Immunity During Sepsis

Compartmentalization of cAMP Signaling in Mesangial Cells by Phosphodiesterase Isozymes PDE3 and PDE4 REGULATION OF SUPEROXIDATION AND MITOGENESIS

Proenkephalin system in human polymorphonuclear cells. Production and release of a novel 1.0-kD peptide derived from synenkephalin.

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