{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T15:11:11Z","timestamp":1779376271527,"version":"3.53.1"},"reference-count":17,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2020,11,20]],"date-time":"2020-11-20T00:00:00Z","timestamp":1605830400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Exp Pharma Physio"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>PDE4 inhibitors are involved in anti\u2010inflammatory and immunomodulatory responses. Recently, they have been getting attention as a new class of drugs treating inflammatory airway diseases. The T lymphocyte is a major cell type present in the inflammatory infiltrate in the airway wall in patients with chronic obstructive pulmonary disease (COPD), and a previous study found that treatment with a PDE4 inhibitor significantly suppressed T cell proliferation. However, the mechanism of action of PDE4 inhibitors has not been elucidated. The present study aimed to investigate major signal transduction pathways of T lymphocyte and identify the phase, during which PDE4 inhibitors affect T cell proliferation. Isolated splenic CD4+ T cells were grown under stimulation with an anti\u2010CD3\/CD28 antibody, and\/or treated with roflumilast\u2010n\u2010oxide (RNO). A western blot assay was performed using major antibodies including anti\u2010p\u201038, anti\u2010p\u2010PI3K, anti\u2010p\u2010JNK, anti\u2010p\u2010ERK 1\/2, anti\u2010NFAT1 (NFATc2), and anti\u2010NF\u2010kB antibodies. Additional experiments conducted on the pathway showed significant change following RNO treatment, thus providing further evidence for signal transduction pathway concerning PDE4 inhibitors. T cell proliferation was suppressed by RNO treatment. In the pathways involved in T cell proliferation, only expression of anti\u2010NFAT1 antibody was suppressed by RNO treatment. In additional experiments on the NFAT pathway, the very first phase (TCR signalling) remained unchanged on treatment with RNO, but RNO treatment increased IP3R expression and suppressed calcineurin activity. Calcineurin activity, reduced by RNO, increased on treatment with an IP3 receptor agonist. PED4 inhibitor, roflumilast is speculated to suppress T cell proliferation by interfering with IP3\u2010IP3R binding to inhibit calcium emission, blocking pathway activation from this phase onward, eventually decreasing the level of a growth factor for T cell proliferation, IL\u20102.<\/jats:p>","DOI":"10.1111\/1440-1681.13417","type":"journal-article","created":{"date-parts":[[2020,10,12]],"date-time":"2020-10-12T05:18:20Z","timestamp":1602479900000},"page":"221-226","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The effect and associated mechanism of action of phosphodiesterase 4 (PDE4) inhibitor on CD4+ lymphocyte proliferation"],"prefix":"10.1111","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5460-2005","authenticated-orcid":false,"given":"Shin Young","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Internal Medicine St. Vincent\u2019s Hospital The Catholic University of Korea  Suwon Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tai Joon","family":"An","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Yeouido St. Mary\u2019s Hospital The Catholic University of Korea  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4533-7937","authenticated-orcid":false,"given":"Chin Kook","family":"Rhee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Seoul St. Mary\u2019s Hospital The Catholic University of Korea  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chan Kwon","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Yeouido St. Mary\u2019s Hospital The Catholic University of Korea  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Hye","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Yeouido St. Mary\u2019s Hospital The Catholic University of Korea  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"HyoungKyu","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Yeouido St. Mary\u2019s Hospital The Catholic University of Korea  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,11,20]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201301-0021PP"},{"issue":"4","key":"e_1_2_8_3_1","first-page":"531","article-title":"Role of T\u2010lymphocytes and pro\u2010inflammatory mediators in the pathogenesis of chronic obstructive pulmonary disease","volume":"3","author":"Gadgil A","year":"2008","journal-title":"Int J Chron Obstruct Pulmon 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