Intracellular compartmentalization of leukotriene synthesis: unexpected nuclear secrets

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/116963/1/feb2s0014579300023747.pd

Inhibition of protein translation as a novel mechanism for prostaglandin E2 regulation of cell functions

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154239/1/fsb2028001008.pd

Protein kinase A inhibition of macrophage maturation is accompanied by an increase in DNA methylation of the colonyâ stimulating factor 1 receptor gene

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134212/1/imm12641.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134212/2/imm12641_am.pd

Regulation of alveolar macrophage p40phox: hierarchy of activating kinases and their inhibition by PGE2

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141717/1/jlb0219.pd

Cysteinyl leukotrienes as novel host factors facilitating Cryptococcus neoformans penetration into the brain

Cryptococcus neoformas infection of the central nervous system (CNS) continues to be an important cause of mortality and morbidity, and a major contributing factor is our incomplete knowledge of the pathogenesis of this disease. Here, we provide the first direct evidence that C. neoformans exploits host cysteinyl leukotrienes (LTs), formed via LT biosynthetic pathways involving cytosolic phospholipase A2α (cPLA2α) and 5â lipoxygenase (5â LO) and acting via cysteinyl leukotriene type 1 receptor (CysLT1), for penetration of the bloodâ brain barrier. Gene deletion of cPLA2α and 5â LO and pharmacological inhibition of cPLA2α, 5â LO and CysLT1 were effective in preventing C. neoformans penetration of the bloodâ brain barrier in vitro and in vivo. A CysLT1 antagonist enhanced the efficacy of an antiâ fungal agent in therapy of C. neoformans CNS infection in mice. These findings demonstrate that host cysteinyl LTs, dependent on the actions of cPLA2α and 5â LO, promote C. neoformans penetration of the bloodâ brain barrier and represent novel targets for elucidating the pathogenesis and therapeutic development of C. neoformans CNS infection.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136343/1/cmi12661_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136343/2/cmi12661.pd

Glucocorticoid receptors are required for up‐regulation of neuronal 5‐lipoxygenase (5LOX) expression by dexamethasone

5‐lipoxygenase (5LOX) is the key enzyme in the synthesis of leukotrienes from arachidonic acid. Hyperglucocorticoidemia, dexamethasone, and aging up‐regulate 5LOX in the brain, including the cerebellum in vivo. We studied the mechanisms of dexamethasone‐triggered 5LOX up‐regulation in primary cultures of rat cerebellar granule neurons (CGN). We measured 5LOX mRNA and protein contents, and the formation of cysteinyl leukotrienes (LTC4, LTD4, and LTE4). The dexamethasone (0.1 μM or 1 μM)‐increased 5LOX mRNA and protein contents were already observed at 3 h of treatment, and they persisted for at least 24 h. Dexamethasone also increased the content of cysteinyl leukotrienes, assayed in the presence of 2 μM calcium ionophore A23187 and 10 μM arachidonic acid. The stimulatory effect of dexamethasone on 5LOX expression was inhibited by the glucocorticoid receptor (GR) antagonist RU486 and by reducing the CGN content of GR receptor protein with a GR‐specific antisense oligonucleotide. The 5LOX mRNA half‐life was longer in dexamethasone than in vehicle‐treated CGNs. Our results indicate that dexamethasone increases 5LOX expression in CGNs in a GR‐dependent manner and that it also increases the stability of 5LOX mRNA. Further studies are warranted to elucidate the physiologic/pathologic significance of glucocorticoid‐regulated expression of 5LOX in the central nervous system.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154349/1/fsb2fj000836fje-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154349/2/fsb2fj000836fje.pd

NADPH oxidase deficiency results in reduced alveolar macrophage 5â lipoxygenase expression and decreased leukotriene synthesis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141933/1/jlb1585.pd

Polycyclic aromatic hydrocarbons present in cigarette smoke cause endothelial cell apoptosis by a phospholipase A2dependent mechanism

Smoking is a major risk factor for endothelial cell injury and subsequent coronary artery disease. Epidemiological studies implicate the phospholipase A2/arachidonic acid cascade in the mechanism by which smoking causes heart disease. However, specific components of cigarette smoke that activate this pathway have not been identified. The purpose of this study was to investigate the effects of polycyclic aromatic hydrocarbons contained in cigarette smoke on phospholipase A2 (PLA2) activity and apoptosis of human coronary artery endothelial cells. 1methylanthracene (1â MA), phenanthrene (PA), and benzo(a)pyrene (B(a)P) caused significant release of 3Hâ arachidonate from endothelial cells. 1â MA and PA, but not B(a)P, also caused significant release of 3Hâ linoleic acid. Release of fatty acids from membrane phospholipids preceded the onset of apoptosis. 3Hâ arachidonate release and apoptosis induced by 1â MA, B(a)P, and PA were inhibited by methylarachidonoylâ fluorophosphonate, an inhibitor of Groups IV and VI PLA2s. Bromoenol lactone, an inhibitor of Group VI enzymes, inhibited both 3Hâ arachidonate release and apoptosis induced by 1â MA and PA, but not B(a)P. MJ33, an inhibitor of the acidic calciumâ independent PLA2, attenuated 3Hâ arachidonate release and apoptosis by PA, but not 1MA or B(a)P. The presence of Groups IV and VI and the acidic iPLA2 in endothelial cells was demonstrated by reverse transcriptaseâ polymerase chain reaction and Western analysis. These data suggest that 1â MA, B(a)P and PA induce apoptosis of endothelial cells by a mechanism that involves activation of these three distinct isoforms of PLA2.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154505/1/fsb2fasebj16110092-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154505/2/fsb2fasebj16110092.pd

Leukotriene B4 enhances the generation of proinflammatory microRNAs to promote MyD88-dependent macrophage activation

MicroRNAs are known to control TLR activation in phagocytes. We have shown that leukotriene (LT) B4 (LTB4) positively regulates macrophage MyD88 expression by decreasing suppressor of cytokine signaling-1 (SOCS-1) mRNA stability. In this study, we investigated the possibility that LTB4 control of MyD88 expression involves the generation of microRNAs. Our data show that LTB4, via its receptor B leukotriene receptor 1 (BLT1) and Gαi signaling, increased macrophage expression of inflammatory microRNAs, including miR-155, miR-146b, and miR-125b. LTB4-mediated miR-155 generation was attributable to activating protein-1 activation. Furthermore, macrophage transfection with antagomirs against miR-155 and miR-146b prevented both the LTB4-mediated decrease in SOCS-1 and increase in MyD88. Transfection with miR-155 and miR-146b mimics decreased SOCS-1 levels, increased MyD88 expression, and restored TLR4 responsiveness in both wild type and LT-deficient macrophages. To our knowledge, our data unveil a heretofore unrecognized role for the GPCR BLT1 in controlling expression of microRNAs that regulate MyD88-dependent activation of macrophages