The role of inflammatory cytokines and ERK1/2 signaling in chronic prostatitis/chronic pelvic pain syndrome with related mental health disorders

Chao Hu,Yinying Dong,Yehao Dong,Ching-Shwun Lin,Jiefeng Cui,Jican Dai,Xiang Chen,Hualan Yang,Tongyu Zhu,Yanfang Zhao,Long Li,Ping Zheng

doi:10.1038/srep28608

Abstract

Mental health disorders(MHD) in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) have been widely studied. 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 = 810) and control subjects (n = 992) 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-1α, 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 cerebrospinal fluid. In behavioral tests, CP/CPPS rats showed anxiety- and 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, but not caudate nucleus. Thus, 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/CPPS-related MHD.

Highlights

Support that autoimmunity is a major cause of dysfunction of the organs involved in CP/CPPS in both humans and in rodent models of autoimmune CP/CPPS12–15
Baseline clinical and mental parameters of recruited control subjects and CP/CPPS patients revealed no significant differences in age and BMI (Table 1)
The present study comprising 810 CP/CPPS patients with mental health disorders (MHD) and 992 control subjects showed significantly more anxiety and depression with higher Self Anxiety Scale (SAS) and Self Depression Scale (SDS) scores observed in CP/CPPS patients compared with normal control subjects, which was consistent with the previous reports[32,33,34]

Summary

Introduction

Support that autoimmunity is a major cause of dysfunction of the organs involved in CP/CPPS in both humans and in rodent models of autoimmune CP/CPPS12–15. There is no study evaluating anxiety levels and depression-like behavior, and their correlation with inflammatory cytokine levels in human CP/CPPS or rodent models. Over the last decades neuroscience research has identified specific brain areas, such as the basolateral amygdala (BLA), nucleus accumbens (NAc), hippocampus (Hippo), and caudate nucleus (Cau), which are related to anxiety, depression, and spatial and associative memory[22,23,24,25]. Several reports have shown that the dysfunction of synaptic plasticity in the above brain areas is related to brain dysfunctions, such as anxiety, depression, and memory impairment[27,28,29]. Behavioral performance of anxiety and depression, learning and memory disturbances, cytokine levels in prostates and cerebrospinal fluid (CSF), and alterations of ERK1/2 signaling were studied in specific brain areas in a rodent model of CP/CPPS

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