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However, the underlying role of inflammatory cytokines and their associated signaling pathways have not been investigated. Here, we report the potential role of cytokines and associated signaling pathways in CP\/CPPS patients with MHD and in a CP\/CPPS animal model. CP\/CPPS patients (n\u2009=\u2009810) and control subjects (n\u2009=\u2009992) were enrolled in this case-control multicenter study, and serum cytokine levels were measured. Male Sprague-Dawley rats received multiple intracutaneous injections of an immuno-agent along with a pertussis-diphtheria-tetanus triple vaccine for autoimmune CP\/CPPS development. The results revealed that, in CP\/CPPS patients with significant MHD, elevated IL-1\u03b1, IL-1\u03b2, IL-4, IL-13, and TNF-\u03b1 serum levels were observed. The above five cytokines in CP\/CPPS rats were significantly elevated in prostate tissue (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), and IL-1\u03b2 levels were elevated in serum and cerebrospinal fluid. In behavioral tests, CP\/CPPS rats showed anxiety- and depression-like symptoms, and impaired spatial and associative memory performance (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). In the CP\/CPPS group, ERK1\/2 phosphorylation levels were increased in the amygdala and nucleus accumbens, and decreased in the hippocampus, but not caudate nucleus. Thus, prostate-derived cytokines, especially IL-1\u03b2, cross the blood brain barrier and may lead to enhanced ERK1\/2 signaling in several brain areas, possibly underlying induction of CP\/CPPS-related MHD.<\/jats:p>","DOI":"10.1038\/srep28608","type":"journal-article","created":{"date-parts":[[2016,6,23]],"date-time":"2016-06-23T18:27:57Z","timestamp":1466706477000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["The role of inflammatory cytokines and ERK1\/2 signaling in chronic prostatitis\/chronic pelvic pain syndrome with related mental health disorders"],"prefix":"10.1038","volume":"6","author":[{"given":"Chao","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hualan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinying","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yehao","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiefeng","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongyu","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Shwun","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jican","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,6,23]]},"reference":[{"key":"BFsrep28608_CR1","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1001\/jama.282.3.236","volume":"282","author":"JN Krieger","year":"1999","unstructured":"Krieger, J. 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