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M M Billah

Publications and source records attributed to M M Billah.

At least 19 recordsLinked to original sources
PubMed1995

Transcription of the murine interleukin 5 gene is regulated by multiple promoter elements.

Cis-acting regions in the 5'-flank of the mouse interleukin 5 (IL-5) gene involved in the specific and inducible regulation of IL-5 transcription in an untransformed mouse T cell clone, D10.G4.1, have been identified. Transient transfection assays with a series of deletion IL-5 promoter reporter constructs indicate that multiple regulatory elements in the 5'-flanking region of the IL-5 promoter play a role in regulating IL-5 transcription in Th2 cells. Negatively acting elements, NRE I and NRE II, map to the regions between positions -431 and -392 and positions -300 and -261. A positive regulatory element has been mapped to the region between positions -224 and -81. The activity of these elements is dependent on activation of the cells. A 40-bp sequence within this region, termed the IL-5 PRE, has been shown to bind at least two specific nuclear protein complexes from unstimulated and stimulated D10.G4.1 cells. An additional protein complex specific for this site has been identified in nuclear fractions from cells stimulated in the presence of the protein synthesis inhibitor, cycloheximide. Proteins that bind to these elements are likely to be important inducible and specific factors essential for control of IL-5 transcription in response to T cell receptor-mediated signaling events.

Animals↗
PubMed1995

Interferon-alpha down-regulates the interleukin-6 receptor in a human multiple myeloma cell line, U266.

The effects of interferon-alpha (IFN-alpha) on the interleukin-6 (IL-6) receptor in a multiple myeloma cell line, U266, have been examined. IFN-alpha inhibits [3H]thymidine incorporation in U266 cells in a time- and dose-dependent manner. Furthermore, IFN-alpha inhibits the ability of IL-6 to induce increases in [3H]thymidine incorporation. While IFN-alpha suppresses the ability of 125I-IL-6 to bind to the IL-6 receptor on U266 cells, this effect is not due to competition of IFN-alpha with IL-6 for the IL-6 receptor. Although IFN-alpha induces IL-6 synthesis in the U266 cell, inhibition of IL-6 binding occurs when IL-6 synthesis is minimal. Furthermore, after pretreatment of U266 cells with neutralizing anti-IL-6 antibodies, IFN-alpha still inhibits 125I-IL-6 binding. These data suggest that IFN-alpha inhibition of 125I-IL-6 binding does not involve IL-6 synthesis. IFN-alpha reduces 125I-IL-6 binding without affecting its affinity, suggesting that IFN-alpha inhibits IL-6 receptor expression. Although pretreatment with cycloheximide inhibits 125I-IL-6 binding, IFN-alpha does not cause a selective decrease in the levels of gp130 or IL-6 receptor mRNA at times when 125I-IL-6 binding is inhibited. These observations indicate that IFN-alpha lowers IL-6 receptor density on U266 cells by mechanisms other than competitive binding or lowering IL-6 receptor mRNA production. Receptor down-regulation may be a mechanism of IFN-alpha-induced inhibition of growth in U266 cells.

Cell Division↗
PubMed1995

Interleukin (IL)-10 inhibits nuclear factor kappa B (NF kappa B) activation in human monocytes. IL-10 and IL-4 suppress cytokine synthesis by different mechanisms.

Our previous studies in human monocytes have demonstrated that interleukin (IL)-10 inhibits lipopolysaccharide (LPS)-stimulated production of inflammatory cytokines, IL-1 beta, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha by blocking gene transcription. Using electrophoretic mobility shift assays (EMSA), we now show that, in monocytes stimulated with LPS or TNF alpha, IL-10 inhibits nuclear stimulation of nuclear factor kappa B (NF kappa B), a transcription factor involved in the expression of inflammatory cytokine genes. Several other transcription factors including NF-IL-6, AP-1, AP-2, GR, CREB, Oct-1, and Sp-1 are not affected by IL-10. This selective inhibition by IL-10 of NF kappa B activation occurs rapidly and in a dose-dependent manner and correlates well with IL-10's cytokine synthesis inhibitory activity in terms of both kinetics and dose responsiveness. Furthermore, compounds such as tosylphenylalanyl chloromethyl ketone and pyrrolidinedithiocarbamate that are known to selectively inhibit NF kappa B activation block cytokine gene transcription in LPS-stimulated monocytes. Taken together, these results suggest that inhibition of NF kappa B activation may be an important mechanism for IL-10 suppression of cytokine gene transcription in human monocytes. IL-4, another cytokine that inhibits cytokine mRNA accumulation in monocytes, shows little inhibitory effect on LPS-induced NF kappa B activation. Further examination reveals that, unlike IL-10, IL-4 enhances mRNA degradation and does not suppress cytokine gene transcription. These data indicate that IL-10 and IL-4 inhibit cytokine production by different mechanisms.

Cytokines↗
PubMed1995

Relationship of phospholipase C- and phospholipase D-mediated phospholipid remodeling pathways to respiratory burst activation in human neutrophils stimulated by Candida albicans hyphae.

Neutrophil (PMN) oxidant release, a key component of defenses against disseminated candidiasis, was preceded by oxidant generation after stimulation by Candida albicans hyphae. Opsonized or unopsonized hyphae triggered phospholipase D (PLD) activation within 5 or 30 s, respectively, forming 1-O-alkyl-phosphatidic acid (alkyl-PA) or 1-O-alkyl-phosphatidyl-ethanol in the presence of ethanol. Ethanol, which competitively lowers phosphatidic acid (PA) production, caused dose-dependent inhibition of superoxide (O2-) generation after hyphal stimulation but altered neither baseline-unstimulated O2- production nor responses to phorbol myristate acetate. PA rises evoked by unopsonized hyphae began 2 min before significant O2- release, also preceding both phospholipase C activation and cytosolic Ca2+ rises. Diacylglycerol (DAG) rose in two distinct phases after stimulation by opsonized or unopsonized hyphae, peaking briefly after 60 or 120 s, respectively, followed by prolonged secondary rises. Initial DAG rises preceded inositol triphosphate elevations evoked by unopsonized hyphae. Though PA rose before DAG, no dephosphorylation of PA to form 1-O-alkyl-DAG was noted. Propranalol, which increases PA accumulation by inhibiting PA phosphohydrolase, lowered PMN O2- responses to hyphae. Early DAG rises temporally overlapped respiratory burst initiation but PMN responses to hyphae were unchanged by a DAG kinase inhibitor, R59022, which blocks phosphorylation of DAG to PA and enhances DAG accumulation. Thus, neither PA nor DAG accumulation individually accounted for triggering PMN O2- responses to hyphae. PLD activation and PA production may facilitate PMN fungicidal responses to hyphae but play an indirect role in initiating the respiratory burst.

Candida albicans↗
PubMed1992

Differential plasma duration of antiplatelet-activating factor and antihistamine activities of oral Sch 37370 in humans.

Preclinical studies have established that Sch 37370 (1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cyclohepta [1,2-b]pyridin-11-ylidene)piperidine) is an orally active antagonist of platelet-activating factor (PAF) and histamine H1-receptors with potential therapeutic use in the treatment of asthma. To evaluate the efficacy and duration of anti-PAF and antihistamine actions of oral Sch 37370 in humans, a single dose (5 mg/kg) of Sch 37370 was given orally to each of 10 male subjects in a placebo-controlled, double-blind crossover study. Blood samples were drawn before and at various times (2 to 48 hours) after Sch 37370 or placebo. Plasma samples were analyzed for Sch 37370 by a gas chromatographic method, for the anti-PAF activity by measuring the aggregation of platelets stimulated with PAF, and for the antihistamine activity by measuring displacement of [3H]pyrilamine from rat brain membrane binding sites. The plasma anti-PAF activity declined from high levels at 2 hours to barely detectable levels at 24 hours; however, significant activity was still present at 12 hours. The plasma levels of Sch 37370 closely paralleled the anti-PAF profile. The plasma antihistamine activity reached a maximum within 2 to 8 hours and declined thereafter. However, 48 hours after Sch 37370, the antihistamine activity was still present at a significant level in most subjects. It is concluded that, in humans, oral Sch 37370 antagonizes both PAF and histamine with plasma antihistamine activity lasting longer than plasma anti-PAF activity.

Administration, Oral↗
PubMed1991

Wheat germ agglutinin and other selected lectins increase synthesis of decay-accelerating factor in human endothelial cells.

Decay accelerating factor (DAF) is a cell-surface phosphatidylinositol-anchored protein that protects the cell from inadvertent complement attack by binding to and inactivating C3 and C5 convertases. We have measured DAF on human umbilical vein endothelial cells (HUVEC) by immunoradiometric assay after its removal by phosphatidylinositol-specific phospholipase C or Nonidet P-40 detergent extraction and have previously demonstrated that DAF synthesis can be stimulated by phorbol ester activation of protein kinase C. We now report that although stimulation (4-48 h) of HUVEC with various cytokines, including TNF, IL-1, and IFN-gamma, did not alter DAF levels, wheat germ agglutinin (WGA) (5-50 micrograms/ml), a lectin specific for binding N-acetyl neuraminic acid and N-acetyl glucosamine residues, increased DAF levels fivefold when incubated with HUVEC for 12 to 24 h. The lectins Con A and PHA also stimulated DAF expression twofold, whereas a number of others including Ulex europaeus, Bandeiraea simplicifolia lectin I, and Ricinus communis agglutinin I, which bind to endothelial cells, were inactive. The increase in DAF by WGA was inhibited by N-acetyl glucosamine (10-50 mM) but by neither N-acetyl neuraminic acid nor removal of surface N-acetyl neuraminic acid with neuraminidase. However, succinylated WGA, which has unaltered affinity for N-acetyl glucosamine but not longer binds N-acetyl neuraminic acid, was inactive. These data suggest that the binding of WGA to sugar residues alone is not sufficient to trigger DAF expression and that occupation of additional, specific sites are required. The increase in DAF levels on HUVEC was blocked by inhibitors of RNA and protein synthesis. We conclude that continuous occupation by WGA of specific binding sites on HUVEC triggers events leading to DAF synthesis. This unique, long term stimulation of endothelial cells by lectins may be relevant to cell:cell interactions at the endothelium.

Antigens, CD↗
PubMed1991

Existence of cytosolic phospholipase D. Identification and comparison with membrane-bound enzyme.

In a wide variety of cells, phosphatidylcholine hydrolysis in response to diverse agents is catalyzed by phospholipase D (PLD) activities that are believed to be membrane-bound. Indeed, PLD has been detected in membrane fractions of several tissues and cells. We now demonstrate in various bovine tissue including lung, brain, spleen, heart, kidney, thymus, and liver as well as rat lung that a great majority of the detectable PLD activity is cytosolic. This cytosolic PLD activity differs from a less abundant membrane-bound isozyme by chromatographic mobilities on anion exchange and gel filtration columns, by substrate specificity, by substrate concentration dependence, and by divalent cation and detergent effects. Fractionation of the cytosol by anion exchange chromatography enhances PLD activity up to 20-fold, suggesting the presence in the cytosol of PLD inhibitory factor(s). We conclude that mammalian PLD exists in multiple forms and that appropriate selection of assay conditions is critical for observing PLD activity in the cytosol.

Animals↗
PubMed1991

Sequential degradation of choline phosphoglycerides by phospholipase D and phosphatidate phosphohydrolase in dibutyryl cAMP-differentiated U937 cells.

Dibutyryl-cAMP-differentiated U937 cells incorporate alkyllyso-sn-glycero-3-[32P]phosphocholine (alkyllyso-[32P]GPC) into cellular alkylacyl-sn-glycero-3-phosphocholine (alkylacyl-GPC). Upon stimulation with fMet-Leu-Phe (fMLP), recombinant C5a, or phorbol 12-myristate 13-acetate (PMA), these cells produce alkylacyl-sn-glycero-3-[32P]phosphate (alkylacyl-[32P]GP). In the presence of ethanol (0.5%), alkylacyl-sn-glycero-3-[32P]phosphoethanol (alkylacyl-[32P]GPet) is also formed with a concomitant reduction in alkylacyl-[32P]GP accumulation. Because cellular ATP is not labeled with 32P, alkylacyl-[32P]GP and alkylacyl-[32P]GPet must be formed by phospholipase D (PLD)-catalyzed hydrolysis and transphosphatidylation, respectively. Activation by receptor agonists, but not by PMA, requires extracellular Ca2+ and is augmented by cytochalasin B pretreatment. Upon stimulation, dibutryl cAMP-differentiated U937 cells labeled with alkylacyl-[32P]GPC produce [32P]PO4 but not [32P]phosphocholine. Furthermore, when these cells were labeled in alkylacyl-GPC by incubation with [3H]alkyllyso-GPC and then stimulated, [3H]alkylacyl-glycerol ([3H]alkylacyl-Gro) is produced with a time-course similar to that of [32P]PO4 formation and coincident with the decline in alkylacyl-GP accumulation. These results demonstrate that alkylacyl-GP formed by PLD is dephosphorylated by phosphatidate phosphohydrolase to produce PO4 and alkylacyl-Gro. Upon stimulation with fMLP or C5a, U937 cells labeled in diacyl-sn-glycero-3-phosphocholine (diacyl-GPC) by incubation with [3H]acyllyso-GPC generate [3H]diacyl-GP, [3H]diacyl-GPEt, and [3H]diacyl-Gro with kinetics similar to those for the generation of the [3H]alkyl products. Thus, in differentiated U937 cells stimulated with receptor agonists, both alkylacyl-GPC and diacyl-GPC are sequentially metabolized by PLD and phosphatidate phosphohydrolase.

Animals↗
PubMed1991

Granulocyte phospholipase D is activated by a guanine nucleotide dependent protein factor.

When post-nuclear homogenates from HL-60 granulocytes are incubated in the presence of CaCl2, GTP gamma S and ethanol, phospholipase D (PLD) metabolizes both exogenous 2-[14C]arachidonyl-phosphatidylcholine and endogenous phosphatidyl[3H]choline to produce 2-[14C]arachidonyl-phosphatidic acid, 2-[14C]arachidonyl-phosphatidylethanol and [3H]choline. Fractionation of the homogenate by ultracentrifugation into cytosolic and membrane fractions results in the loss of PLD activity. However, when these two fractions are combined in the same proportion as found in the unfractionated homogenate, PLD activity is completely restored. This activity is proportional to the concentration of both the cytosol and the particulate fractions. Release of [14C]arachidonate by PLA2 that occurs under these assay conditions does not require the combined presence of cytosol and membrane fractions. We conclude that, in granulocyte homogenates, PLD activity but not arachidonate release, exhibits an essential requirement for a heat-labile factor whose activity depends on the presence of GTP gamma S.

Calcium↗
PubMed1991

Sphingosine inhibits phosphatidate phosphohydrolase in human neutrophils by a protein kinase C-independent mechanism.

Human neutrophils have been labeled in 1-O-alkyl-phosphatidylcholine with 3H in both the alkyl chain and the choline moiety. Upon stimulation of these labeled cells with formyl-Met-Leu-Phe, C5a, or phorbol 12-myristate 13-acetate, phospholipase D is activated to produce 1-O-[3H]alkylphosphatidic acid ([3H]alkyl-PA) and [3H]choline. The [3H]alkyl-PA is then dephosphorylated by phosphatidate phosphohydrolase (PPH) to produce 1-O-[3H]alkyldiglyceride ([3H]alkyl-DG). Sphingosine, a sphingoid base known to inhibit protein kinase C (PKC), causes a dose-dependent inhibition of [3H]alkyl-DG formation. This inhibition is accompanied by increased accumulation of [3H]alkyl-PA without alterations in [3H]choline formation. Studies using various other sphingoid bases demonstrate that a long hydrocarbon chain and an amino group are required for the inhibition of DG formation. These results suggest that sphingoid bases inhibit PPH activity without altering phospholipase D activation and that they exhibit a similar structure-activity relationship for both PPH and PKC. K252a, a PKC inhibitor which acts by competing for ATP binding sites, does not inhibit the formation of [3H]alkyl-DG, [3H]alkyl-PA, or [3H]choline at a concentration (3 microM) that completely blocks phorbol 12-myristate 13-acetate-induced protein phosphorylation. Moreover, in neutrophil homogenates, sphingosine but not octylamine, inhibits PPH activity in a dose-dependent manner. Thus sphingosine inhibits PPH activity by a PKC-independent mechanism, raising the possibility that sphingoid bases may play a role in regulating PPH-mediated lipid metabolism in stimulated cells.

Adenosine Triphosphate↗
PubMed1991

Discovery and preliminary pharmacology of Sch 37370, a dual antagonist of PAF and histamine.

From a series of amide analogs of the histamine H1 antagonist, azatadine, a potent, orally active, dual platelet-activating factor (PAF) and histamine antagonist, Sch 37370, namely 1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo- [5,6]cyclohepta[1,2-b]pyridin-11-ylidine)piperidine, was discovered. Sch 37370 selectively inhibits PAF-induced aggregation of human platelets in vitro (IC50 = 0.6 microM), and in vivo inhibits PAF- and histamine-induced bronchospasm in guinea pigs with ED50 values of 6.0 and 2.4 mg/kg p.o., respectively. Sch 37370 is expected to be more efficacious than single mediator antagonists in allergic diseases, such as asthma.

Histamine Antagonists↗
PubMed1991

Role of phospholipase in generating lipid second messengers in signal transduction.

Many lipids or lipid-derived products generated by phospholipases acting on phospholipids in membranes are implicated as mediators and second messengers in signal transduction. Our current understanding of the primary sequence relationships within the class of extracellular phospholipase A2's and among the numerous forms of the mammalian phosphatidylinositol-specific phospholipase C's is reviewed. New results suggesting roles for these phospholipases as well as other phospholipases such as phospholipase C and D acting on phosphatidlycholine in generating arachidonic acid for eicosanoid biosynthesis, inositol phosphates for Ca2+ mobilization, and diglyceride for protein kinase C activation through receptor-mediated processes, are discussed. In addition, the possible role of phospholipases acting on sphingolipids such as sphinglomyelinase in generating lipid mediators is considered.

Arachidonic Acid↗
PubMed1991

Sch 37370: a new drug combining antagonism of platelet-activating factor (PAF) with antagonism of histamine.

Multiple mediators are involved in the pathophysiology of allergic and inflammatory disorders. Drugs that affect the action of more than one mediator may, therefore, be particularly effective in these disorders. Two such mediators are platelet-activating factor (PAF) and histamine. From a structural series with documented antihistamine activity, Sch 37370 has been identified as a dual antagonist of PAF and histamine. In vitro, Sch 37370 selectively inhibits PAF-induced aggregation of human platelets (IC50 = 0.6 microM) and also competes with PAF binding to specific sites in membrane preparations from human lungs (IC50 = 1.2 microM). Sch 37370 also blocks the binding of [3H]pyrilamine to histamine H1 receptors in rat brain membranes. In guinea pigs, orally administered Sch 37370 is effective against bronchospasm to histamine (ED50 = 2.4 mg/kg), PAF (ED50 = 6.0 mg/kg) or serotonin (ED50 = 9.6 mg/kg). In contrast, it only weakly antagonizes methacholine-induced bronchospasm (ED50 = 51 mg/kg) and is totally inactive at 50 mg/kg against bronchospasm due to leukotriene C4 or substance P. Sch 37370 blocks hypotension in rats and a cutaneous reaction in monkeys induced by either PAF or histamine, as well as PAF-induced edema in the rat pleural cavity. In addition, Sch 37370 blocks bronchospasm induced by either antigen in sensitized guinea pigs or hyperventilation in nonsensitized guinea pigs. Sch 37370 also inhibits antigen-induced lung eosinophilia in sensitized guinea pigs and a reverse passive Arthus reaction in rats. Although Sch 37370 is not the most potent PAF antagonist or antihistamine, it is the first compound that combines these pharmacologically relevant activities and may offer important advantages over currently available antihistamine therapies.

Animals↗
PubMed1990

Phorbol-12-myristate-13-acetate activation of phospholipase D in human neutrophils leads to the production of phosphatides and diglycerides.

The contribution of phospholipase D (PLD) to the production of phosphatides (PA) and diglycerides (DG) in phorbol-12-myristate-13-acetate (PMA)-stimulated human neutrophils was studied. Neutrophils were double labeled with 1-O-[3H]alkyl-phosphatidylcholine [( 3H]alkyl-PC) and alkyl-[32P]PC. Upon stimulation with PMA, these cells produced 1-O-alkyl-PA (alkyl-PA) and, in the presence of ethanol, 1-O-alkyl-phosphatidylethanol (alkyl-PEt) both containing 3H and 32P. Lagging behind alkyl-PA and alkyl-PEt formation was the production of 1-O-[3H]alkyl-diglyceride [( 3H]alkyl-DG) and [32P]orthophosphate [( 32P]PO4), suggesting dephosphorylation of alkyl-PA by PA phosphohydrolase (PPH). Furthermore, the PPH inhibitor, propranolol, inhibited the formation of both [3H]alkyl-DG and [32P]PO4, while increasing alkyl-PA levels (containing both 3H and 32P). PMA-induced DG mass accumulation was also inhibited by propranolol. The results of this study demonstrate that PMA activates PLD in neutrophils leading to the generation of PA and that the bulk of the DG mass accumulation is derived from the sequential actions of PLD and PPH on PC.

Diglycerides↗
PubMed1990

Activation of phospholipase D in normodense human eosinophils.

Normodense human eosinophils have been labeled in 1-0-alkyl-phosphatidylcholine (alkyl-PC) with 32P by incubating isolated cells with alkyl-[32P]lysoPC. Stimulation of these 32P-labeled cells with C5a, A23187 or PMA in the presence of 0.5% ethanol resulted in time- and dose-dependent formation of alkyl-[32P]phosphatidic acid (alkyl-[32P]PA) and alkyl-[32P]phosphatidylethanol (alkyl-[32P]PEt). Because cellular ATP does not contain 32P, alkyl-[32P]PA must have been formed by the hydrolytic action of phospholipase D (PLD) and not by the combined actions of phospholipase C and DG kinase. Regardless of the stimulating agent, alkyl-[32P]PEt formation paralleled that of alkyl-[32P]PA, suggesting that alkyl-PEt was the result of a PLD-catalyzed transphosphatidylation reaction between alkyl-PC and ethanol. These data provide the first definitive proof of receptor- and nonreceptor-mediated activation of PLD in normodense eosinophils derived from human blood.

Calcimycin↗