{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T18:23:28Z","timestamp":1770834208942,"version":"3.50.1"},"reference-count":51,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2009,1,29]],"date-time":"2009-01-29T00:00:00Z","timestamp":1233187200000},"content-version":"vor","delay-in-days":3622,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[1999,3]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>Previous studies have established that glucocorticoids inhibit airway smooth muscle DNA synthesis. The effects of a combination of the pro\u2010inflammatory cytokines, interleukin\u20101\u03b1 (IL\u20101\u03b1) and tumour necrosis factor\u2010\u03b1 (TNF\u2010\u03b1) on the inhibition of DNA synthesis by glucocorticoids in human cultured airway smooth muscle have now been investigated, since these cytokines are chronically expressed in asthmatic airways.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Thrombin (0.3\u2003u\u2003ml<jats:sup>\u22121<\/jats:sup>) and basic fibroblast growth factor (bFGF, 300\u2003p<jats:sc>M<\/jats:sc>) stimulated increases in DNA synthesis which were concentration\u2010dependently inhibited by dexamethasone (1\u20131000\u2003n<jats:sc>M<\/jats:sc>).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The cytokine mixture, comprising IL\u20101\u03b1 (0.01 and 0.1\u2003p<jats:sc>M<\/jats:sc>) and TNF\u2010\u03b1 (3 and 30\u2003p<jats:sc>M<\/jats:sc>), directly evoked increases in DNA synthesis which were attenuated by dexamethasone. However, the cytokine mixture prevented responses to bFGF or thrombin.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Paradoxically, in the presence of the cytokine mixture and bFGF, dexamethasone (1\u20131000\u2003n<jats:sc>M<\/jats:sc>) concentration\u2010dependently increased DNA synthesis. Furthermore, neither dexamethasone (100\u2003n<jats:sc>M<\/jats:sc>) nor fluticasone propionate (1\u2003n<jats:sc>M<\/jats:sc>) inhibited DNA synthesized in response to bFGF\/cytokine mixture combination and dexamethasone was similarly inactive against the thrombin\/cytokine mixture.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The levels of prostaglandin E<jats:sub>2<\/jats:sub> (PGE<jats:sub>2<\/jats:sub>), an established inhibitor of airway smooth muscle DNA synthesis, remained below the limits of assay detection (0.05\u2003n<jats:sc>M<\/jats:sc>) under basal conditions or following stimulation with either thrombin or bFGF. In contrast, the cytokine mixture alone, and in the presence of thrombin or bFGF, induced biologically active levels of PGE<jats:sub>2<\/jats:sub>. Dexamethasone (100\u2003n<jats:sc>M<\/jats:sc>), the non\u2010selective cyclo\u2010oxygenase (COX) inhibitor indomethacin (3\u2003\u03bc<jats:sc>M<\/jats:sc>) or the selective COX\u20102 inhibitor L\u2010745,337 (0.3\u2003\u03bc<jats:sc>M<\/jats:sc>) completely inhibited synthesis of PGE<jats:sub>2<\/jats:sub>.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Neither indomethacin (3\u2003\u03bc<jats:sc>M<\/jats:sc>) nor L\u2010745,337 (0.3\u2003\u03bc<jats:sc>M<\/jats:sc>) influenced thrombin\u2010 or bFGF\u2010induced DNA synthesis. However, each COX inhibitor enhanced DNA synthesis in cytokine\u2010treated cells.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In unstimulated airway smooth muscle cells, COX\u20101, but not COX\u20102 protein was detectable by Western blotting. The induction of COX\u20102 protein by the cytokine mixture was attenuated by dexamethasone (100\u2003n<jats:sc>M<\/jats:sc>), whereas the level of COX\u20101 protein was unaffected by either the cytokines or by dexamethasone.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Cytokine\u2010induced, COX\u20102\u2010dependent eicosanoid production inhibits DNA synthesis. The paradoxical increase in DNA synthesis observed in glucocorticoid treated airway smooth muscle stimulated by cytokine\/bFGF combinations may be explained by the ability of glucocorticoids to repress COX\u20102 induction and prevent cytokine\u2010induction of the DNA synthesis inhibitor, PGE<jats:sub>2<\/jats:sub>.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (1999) <jats:bold>126<\/jats:bold>, 1315\u20131324; doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0702424\">10.1038\/sj.bjp.0702424<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0702424","type":"journal-article","created":{"date-parts":[[2005,1,28]],"date-time":"2005-01-28T19:42:34Z","timestamp":1106941354000},"page":"1315-1324","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Interleukin\u20101\u03b1 and tumour necrosis factor\u2010\u03b1 modulate airway smooth muscle DNA synthesis by induction of cyclo\u2010oxygenase\u20102: inhibition by dexamethasone and fluticasone propionate"],"prefix":"10.1111","volume":"126","author":[{"given":"Ross","family":"Vlahos","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alastair G","family":"Stewart","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,1,29]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1165\/ajrcmb.15.1.8679222"},{"key":"e_1_2_7_3_1","first-page":"S7","article-title":"Effect of corticosteroids on airway hyper\u2010responsiveness","volume":"141","author":"BARNES P.J.","year":"1990","journal-title":"Am. 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