Chronic prostatitis/chronic pelvic pain syndrome: Interplay of inflammatory mediators, "Beyond the Abstract," by Dan Lundh, Hans Hedelin, and Dennis Larsson

BERKELEY, CA ( - The understanding of the pathogenesis of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is poor. Accumulating evidence indicates that CP/CPPS depends on, at least to some degree, inflammatory mediators. The prostate is not always involved; tension myalgia in the inner pelvic floor musculature is a likely culprit.

Previous studies have shown increased pro-inflammatory cytokine level of IL-8 (Interleukin 8) in seminal plasma from CP/CPPS patients, and prostatic secretions show decreased levels of IL-2 (Interleukin 2) and increased levels of IL-10 (Interleukin 10) and TNF-α (tumor necrosis factor alpha). Furthermore, similar studies have also demonstrated increased levels of INF-γ (interferon gamma), IL-2, and IL-10 as well as increased levels of (blood) serum testosterone in CP/CPPS patients compared to controls.

Many diseases featuring long term pain show pathologically altered TNF-α, IL-1β (interleukin 1 beta), and MIF (macrophage inhibitory factor). TNF-α and IL-1β are involved in inducing the COX-2 pathway, which is up-regulated by macrophages. The involvement of the COX pathway is highly interesting since COX-1 is related to homeostatic functions (gastrointestinal tract, renal tract, platelet function, and macrophage differentiation), and COX-2 is related to inflammation.

In our study, we examined inflammatory mediators in blood (plasma) of CP/CPPS that may cause an immune response extending to the circulatory system. The focus in this study was on inflammatory mediators directly or indirectly affecting the COX pathway (Figure 1).

Previously we have shown that stress, especially low temperature, is associated with the pain in CP/CPPS. For typical patients in our study, there was a marked relationship between season and the pain intensity (3 times more severe during the winter months).In our study, we also explored possible effects of parallel diseases and administration of immune responsive drugs to the immune response. In summary, in the circulatory system, MIF showed a significant contribution to CP/CPPS. TNF-α was indicated as a circulatory component when concomitant diseases were excluded. As a general trend, we observed improved significance when excluding factors (drugs and concomitant diseases) that affect the immune system. We did not observe a significant difference in IL-2, TFN-β, IL-1β, cortisol, or testosterone between patients and controls. There were, however, large variations in the TFN-β and IL-1β levels, both in control and patient groups.

A conclusion of the performed study is that CP/CPPS is associated with an immune response extending to the circulatory system. MIF is highlighted as an integral component of the inflammatory response, possibly also extending to TNF-α when removing subjects with concomitant diseases. TNF-α and MIF has previously been suggested as biomarkers for diseases related to chronic pain, and by this study also for CP/CPPS. Despite the presence of inflammatory components in CP/CPPS some issues remain to be addressed: Is the inflammatory cascade the initiation or consequence of CP/CPPS? The MIF cytokine is expressed by cells and tissues that are in direct contact with the environment (lung, skin, gastrointestinal and genitourinary tracts). In addition, it is also expressed by several tissues of the endocrine system (especially in tissues involved in stress responses). It might be possible for temperature stress to induce MIF. But, how does such induction yield a localized (chronic) pain response - why pain in the prostate or pelvic floor musculature and not some other organ? Is the underlying pain feature already residing in the prostate or pelvic floor musculature, and does the induction of MIF only elevate the pain by inducing the COX pathway? Are there other pathways involved? Smooth muscle cells are regulated by prostaglandin products PGE2, TXA2 and PGF2. Reduced blood flow and myalgia have been reported. A muscular spasm (possibly stiffness) in the pelvic floor musculature may be associated with myalgia. However, could prostatic pain share this feature or are there other underlying processes?

The answers to these questions are yet to be determined. It seems likely that the COX pathway and pro-inflammatory mediators play, at least, a fundamental role elevating the pain. The initiation and prolongation of pain is likely to depend on multifaceted factors in which pro-inflammatory cytokines MIF and TNF-α participate.

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Figure 1. Schematic outline of the study. Left, the Cyclooxygenase (COX) pathway which converts arachidonic acid to prostaglandin (prostanoiods) and e.g sensitizes. nociceptor terminals. The middle box (immune system), MIF, IL1-beta and TNF-alpha induce the COX pathway, leading to up-regulated prostaglandins. IL-2 may introduce analgesic effect on nociceptor terminals. To the right, parallel diseases may, depending on the type of disease, alter the homeostasis of the immune system. Perceived stress (psychosocial factors) or induced stress by environmental factors (low temperature) induces MIF. Stress is here associated by cortisol (stress hormone). Testosterone (steroid) has the feature of suppressing generation of pro-inflammatory cytokines.

Written by:
Dan Lundh,a Hans Hedelin,b and Dennis Larssona as part of Beyond the Abstract on This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

aSystems Biology Research Center, School of Life Sciences, University of Skövde, Skövde, Sweden
bDepartment of Research and Development, Skaraborgs Sjukhus, Skövde, Sweden 

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