Objective: Mental health disorders(MHD)in chronic prostatitis/chronic pelvic pain syndrome(CP/CPPS)have been widely studied.However,the underlying molecular mechanisms and,in particular,role of inflammatory cytokines and their associated signaling pathways has not been investigated in detail.To determine the potential role of cytokines and associated signaling pathways in CP/CPPS patients with MHD and in a CP/CPPS animal model.Methods: Between July 2012 and August 2013,810 CP/CPPS patients and 992 control subjects were enrolled in this case-control multicenter study,and serum cytokine levels were measured.Male Sprague-Dawley rats received multiple intracutaneous injections(neck,tail,and pelvic limbs)of an immuno-agent along with a pertussisdiphtheria-tetanus triple vaccine for autoimmune CP/CPPS development.After 45 and 60 days behavioral analysis was performed,and prostate and specific brain areas related to MHD were subjected to RT-qPCR and Western blot analysis of cytokine signaling pathways.Moreover,histological prostate examination,and detection of IL-1β levels in serum and cerebrospinal fluid(CSF)was performed.Results: In CP/CPPS patients with significant MHD,elevated IL-lα,IL-1β,IL-4,IL-13,and TNF-α serum levels were observed.The above five cytokines in CP/CPPS rats were significantly elevated in prostate tissue(P<0.05),and IL-1β levels were elevated in serum and CSE In behavioral tests,CP/CPPS rats showed anxietyand depression-like symptoms,and impaired spatial and associative memory performance(P<0.05).In the CP/CPPS group ERK1/2 phosphorylation levels were increased in the amygdala and nucleus accumbens,and decreased in the hippocampus and caudate nucleus.Lack of human CSF data in present research may limit the translational values of the results.Conclusions: These data suggest that prostate-derived cytokines,especially IL-1β,cross the blood brain barrier and may lead to enhanced ERK1/2 signaling in several brain areas,possibly underlying induction of CP/CPPSrelated MHD.