{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T16:03:23Z","timestamp":1759939403169},"reference-count":51,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2005,11,23]],"date-time":"2005-11-23T00:00:00Z","timestamp":1132704000000},"content-version":"vor","delay-in-days":3706,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Eur J Immunol"],"published-print":{"date-parts":[[1995,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The phosphodiesterase inhibitor oxpentifylline (OXP) has a number of potentially important immunomodulatory actions which include a selective inhibition of the Th1 subset of CD4<jats:sup>+<\/jats:sup> cells <jats:italic>in vitro<\/jats:italic> and inhibition of tumor necrosis factor (TNF)\u2010\u03b1 mRNA transcription. <jats:italic>In vivo<\/jats:italic>, it has a dramatic protective effect against experimental allergic encephalomyelitis. In this animal model, tissue injury is associated with both a Th1 response and with TNF\u2010\u03b1 production, either of which could be targets for the protective action of OXP. In an attempt to clarify the relative importance of the Th cell subsets and TNF\u2010\u03b1 in pathogenesis, we investigated the effect of OXP on a Th2 model of T cell\u2010dependent disease, mercuric chloride (HgCl<jats:sub>2<\/jats:sub>)\u2010induced autoimmunity in the Brown Norway rat. The effects of OXP on the Th1: Th2 response, TNF\u2010\u03b1 mRNA transcription in spleen and ankle joints, and on the incidence and severity of arthritis and cecal vasculitis have been examined and the effects <jats:italic>in vivo<\/jats:italic> have been compared with those of a soluble TNF receptor\u2010IgG1 fusion protein (sTNFR) that neutralizes rat TNF\u2010\u03b1. In two separate experiments, OXP significantly enhanced unstimulated levels of splenic interleukin\u20104 (IL\u20104) mRNA (median 62 %, of an artificial IL\u20104 mRNA construct, <jats:italic>vs.<\/jats:italic> 36.5 % in controls) and in one experiment, exaggerated the total IgE response to HgCl<jats:sub>2<\/jats:sub>. OXP inhibited HgCl<jats:sub>2<\/jats:sub>\u2010induced TNF\u2010\u03b1 mRNA transcription in spleen and ankle joints. In three separate experiments, OXP had a significant protective effect against arthritis, with the mean incidence reduced from 100 % to 30 % and mean peak score reduced from 7.2 to 2.59 (experiments 1 and 2). The protection against arthritis was indistinguishable from that produced by sTNFR. There was no such protection against cecal vasculitis with either OXP or sTNFR. These results demonstrate that OXP induces a shift towards a Th2 response, inhibits TNF\u2010\u03b1 mRNA transcription locally in joint and systemically in spleen, and has a protective effect against arthritis similar to that produced by sTNFR in the HgCl<jats:sub>2<\/jats:sub>\u2010treated BN rat. We conclude that TNF\u2010\u03b1 is a critical cytokine in the pathogenesis of arthritis but not cecal vasculitis in this model, and that inhibition of TNF\u2010\u03b1 transcription is the most important mode of action of OXP in this situation. OXP may be a potential therapeutic agent in the treatment of other arthritides, such as human rheumatoid arthritis, in which TNF\u2010\u03b1 has been implicated in pathogenesis.<\/jats:p>","DOI":"10.1002\/eji.1830251029","type":"journal-article","created":{"date-parts":[[2007,3,1]],"date-time":"2007-03-01T23:39:23Z","timestamp":1172792363000},"page":"2899-2906","source":"Crossref","is-referenced-by-count":15,"title":["Oxpentifylline inhibits tumor necrosis factor\u2010\u03b1 mRNA transcription and protects against arthritis in mercuric chloride\u2010treated Brown Norway rats"],"prefix":"10.1002","volume":"25","author":[{"given":"Patrick D. W.","family":"Kiely","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathleen M.","family":"Gillespie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David B. 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