Abstract Tepoxalin, a compound previously identified as a dual cyclooxygenase/lipoxygenase (CO/LO) inhibitor, is a potent inhibitor of T cell proliferation. Comparing the suppressive effects of tepoxalin and cyclosporin A (CsA) on OKT3-, PMA-, IL-2-, and PMA+ionomycin-induced T cell proliferations revealed marked differences in the mechanism of action between the two compounds. Whereas CsA was most effective in suppressing OKT3-stimulated proliferation, tepoxalin was more potent in inhibiting PMA-, PMA+ionomycin-, and IL-2-induced proliferation. Quantitative PCR (QPCR) assays used to detect cytokine messages showed that tepoxalin blocked IL-2 mRNA transcription in PMA- and PMA+ionomycin-, but not OKT3-stimulated T cells whereas CsA was most potent in inhibiting OKT3-induced IL-2 mRNA induction in these cells. Both tepoxalin and CsA did not inhibit the expression of IL-2R; however, only tepoxalin, but not CsA, inhibited the proliferation of IL-2-dependent blasts and the transcription of IFN-gamma, an IL-2-dependent target gene. Moreover, addition of exogenous IL-2 restored OKT3-induced proliferation to CsA- but not tepoxalin-treated cells. These data suggest that tepoxalin, but not CsA, suppressed T cell proliferation by inhibiting IL-2-induced signal transduction. Consistent with these findings, tepoxalin, unlike CsA, which was most potent when added at the initiation of OKT3 stimulation, was equally active, regardless of whether it was added at the beginning or 48 h after culture initiation. The difference in mechanism of action between tepoxalin and CsA was confirmed further by the synergistic suppressive effects on T cell proliferation upon co-administration of the two compounds.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSynthesis and 5-Lipoxygenase Inhibitory Activities of Some Novel 2-Substituted 5-Benzofuran Hydroxamic AcidsKwasi A. Ohemeng, Mary A. Appollina, Van N. Nguyen, Charles F. Schwender, Monica Singer, Michele Steber, Justin Ansell, Dennis Argentieri, and William HagemanCite this: J. Med. Chem. 1994, 37, 21, 3663–3667Publication Date (Print):October 1, 1994Publication History Published online1 May 2002Published inissue 1 October 1994https://pubs.acs.org/doi/10.1021/jm00047a023https://doi.org/10.1021/jm00047a023research-articleACS PublicationsRequest reuse permissionsArticle Views342Altmetric-Citations43LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
To investigate the role of phospholipase C (PLC) in inflammatory processes, we tested 1-(6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122), a widely used PLC inhibitor, in several in vitro and in vivo assays. We first examined the effects of U73122 on human phospholipase C-β (PLC-β) isozymes and found that U73122 significantly inhibited recombinant human PLC-β2, with an IC50 of ∼6 μM. U73122 had little effect on PLC-β1, PLC-β3, or PLC-β4. Consistent with its ability to inhibit PLC-β2 enzymatic activity, U73122 reduced interleukin-8 and leukotriene B4-induced Ca2+ flux and chemotaxis in human neutrophils in a concentration-dependent manner. In vivo, U73122 blocked carrageenan-induced hind paw edema in rats, carrageenan-induced macrophage and lymphocyte accumulation into subcutaneous chambers in dogs, lipopolysaccharide-induced macrophage, lymphocyte infiltration and prostaglandin E2 production in a mouse peritonitis model, and 12-O-tetradecanoylphorbol-13-acetate-induced ear edema in mice. These results implicate PLC-dependent signaling pathways in the development of acute and chronic inflammatory responses in vivo.
Gastrointestinal irritation is the most significant side effect in patients chronically taking nonsteroidal antiinflammatory drugs (NSAID) for treatment of arthritic conditions. Rioprostil, a primary alcohol prostaglandin E1 analog, prevents gastric bleeding induced by several NSAID in a rat model of arthritis that is similar in many aspects to human rheumatoid arthritis. Daily oral dosing of rioprostil (50 micrograms/kg BID for 15 days) did not influence the course of the adjuvant disease in rats or alter the antiinflammatory or analgesic effect of the NSAID. In a 13 week efficacy study in dogs, rioprostil (40-60 micrograms/kg, PO) completely prevented gastric hemorrhagic lesions induced by daily administration of aspirin.
Abstract 7-Allyl-8-oxoguanosine (loxoribine, 5) was selected from a series of guanosine derivatives for further evaluation as an immunostimulant. Numerous related analogs were also synthesized and evaluated: 2′,3′-ketals of 5 are particularly interesting because they are active, apparently without being cleaved to the free nucleoside.
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