title: Negative feedback between prostaglandin and alpha- and beta-chemokine synthesis in human microglial cells and astrocytes.
abstract: The understanding of immune surveillance and inflammation regulation in cerebral tissue is essential in the therapy of neuroimmunological disorders. We demonstrate here that primary human glial cells were able to produce alpha- and beta-chemokines (IL-8 > growth related protein alpha (GROalpha) >> RANTES > microphage inflammatory protein (MIP)-1alpha and MIP-1beta) in parallel to PGs (PGE2 and PGF2alpha) after proinflammatory cytokine stimulation: TNF-alpha + IL-1beta induced all except RANTES, which was induced by TNF-alpha + IFN-gamma. Purified cultures of astrocytes and microglia were also induced by the same combination of cytokines, to produce all these mediators except MIP-1alpha and MIP-1beta, which were produced predominantly by astrocytes. The inhibition of PG production by indomethacin led to a 37-60% increase in RANTES, MIP-1alpha, and MIP-1beta but not in GROalpha and IL-8 secretion. In contrast, inhibition of IL-8 and GRO activities using neutralizing Abs resulted in a specific 6-fold increase in PGE2 but not in PGF2alpha production by stimulated microglial cells and astrocytes, whereas Abs to beta-chemokines had no effect. Thus, the production of PGs in human glial cells down-regulates their beta-chemokine secretion, whereas alpha-chemokine production in these cells controls PG secretion level. These data suggest that under inflammatory conditions, the intraparenchymal production of PGs could control chemotactic gradient of beta-chemokines for an appropriate effector cell recruitment or activation. Conversely, the elevated intracerebral alpha-chemokine levels could reduce PG secretion, preventing the exacerbation of inflammation and neurotoxicity.
authors.affiliation: Laboratory of Virus, Neuron and Immunity, Unité de Formation et de Recherche, Kremlin Bicêtre, University of Paris-South, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Janabi
authors.forename: I
authors.initials: I
authors.lastname: Hau
authors.forename: M
authors.initials: M
authors.lastname: Tardieu
mesh_terms: D001253:Astrocytes / Q000378:metabolism*; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000096:biosynthesis; D054360:Chemokine CXCL1; D018925:Chemokines / Q000096:biosynthesis*; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000096:biosynthesis; D015237:Dinoprost / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis; D005246:Feedback; D006133:Growth Substances / Q000096:biosynthesis; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis; D017628:Microglia / Q000378:metabolism*; D008954:Models, Biological; D011453:Prostaglandins / Q000096:biosynthesis*; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology