Endogenously opsonized particles divert prostanoid action from lethal to protective in models of experimental endotoxemia.

We report that, in rats, the lethal consequences of high-dose endotoxin challenge are exacerbated by the intravascular administration of prostaglandin E1 but attenuated by the intravascular administration of endocytosable particles. This protection is mediated by opsonins. Nonopsonizable particles were unable to provide protection unless first pseudoopsonized with antibody directed against the CR3 (CD11b/CD18) phagocyte receptor. We show that endogenously opsonized particles can act in concert with prostaglandin E1 (putatively by elevation of neutrophil intracellular cAMP and the resultant downregulation of CR3) to completely rescue animals from the lethal late-stage sequelae of experimental endotoxemia. These data illustrate that the interaction of particles with cellular receptors can transform the overall systemic response to prostaglandin E1 from pro- to antiinflammatory. This suggests a role for multiple receptor engagement events in defining the systemic prostaglandin response and offers a rationale for developing new therapeutic modalities in the treatment of sepsis and other inflammatory diseases.

Monocyte adherence results in selective induction of novel genes sharing homology with mediators of inflammation and tissue repair.

Adherence of monocytes to endothelial cells or extracellular matrices is likely to play a critical role in triggering monocyte activation in extravascular sites of infection, chronic inflammatory disorders, tissue damage and neoplastic growth. We have constructed a cDNA library from monocytes adhered for 30 min on plastic and have screened it by differential hybridization for mRNA rapidly induced by adherence. Two of the cDNA isolated have been identified as IL-1 beta and superoxide dismutase. Sequence data from three other adherence specific clones demonstrates the presence of ATTTA mRNA instability sequences in their 3' untranslated regions signifying inflammation-associated genes. The deduced amino acid sequences indicate the presence of open reading frames with sequence homologies to a family of host defense cytokines, one of them being identified as IL-8. Of the 14 clones initially identified, 4 have been analyzed for induction of mRNA expression. Although 3 of the 4 clones were equally induced by PMA and LPS under nonadherent conditions, all 4 cDNA showed distinct patterns of induction with adherence to extracellular matrix components or endothelial cells. The deduced amino acid sequence homologies indicate that we have isolated cDNA that code for three unique gene products. These cDNA belong to a gene family of early host defense cytokines involved in inflammation and cell growth, but which are differentially regulated by adherence to different surfaces.

Human monocyte inflammatory mediator gene expression is selectively regulated by adherence substrates.

During the process of extravasation, monocytes transiently adhere to capillary endothelium and subsequently with a variety of extracellular matrix components. These early interactions are likely to serve as modifiers of transcriptional activity and serve to prime monocytes for rapid synthesis of mediators. We have previously reported that adherence to plastic rapidly induced or down-regulated steady-state mRNA levels of a number of monocyte inflammatory mediator genes. We now report that adherence to surfaces pretreated with fibronectin resulted in TNF-alpha and CSF-1 mRNA levels approximating adherence to plastic, whereas adherence to fibronectin, fibronectin/anti-fibronectin complexes, or collagen resulted in markedly decreased levels of CSF-1 induction and lysozyme down-regulation. In contrast, monocyte adherence to collagen induced the highest sustained levels of TNF-alpha expression. PMA, but not the chemotactic factor FMLP, stimulated non-adherent monocytes to express c-fos and TNF-alpha and down-regulate lysozyme mRNA. Although all donors responded to adherence, several failed to produce CSF-1 mRNA after PMA stimulation in the non-adherent state. These data demonstrate that monocyte mediator expression may be more dependent on the selectivity of signals induced by adherence to different substrates than the initial chemotactic response.

Cycloartenol-derived sterol biosynthesis in the Peronosporales.

Selected species of the order Peronosporales, which are unable to epoxidize squalene and thus synthesize sterols, are able to metabolize exogenous cycloartenol to lanosterol and in some organisms to fucosterol, ergosterol, and cholesterol. Lanosterol was less effectively utilized but some ergosterol and cholesterol were yielded. Fucosterol was very efficiently metabolized by most species to ergosterol, Delta(7)-ergostenol, Delta(5)-ergostenol, cholestanol, and cholesterol. Several unknown sterols were observed in most trials. These data suggest a vestigial sterol synthetic pathway derived from cycloartenol, followed by possible isomerization to lanosterol and then to other sterols.