Proteinase-Activated Receptor-1 and Immunomodulatory Effects of a PAR1-Activating Peptide in a Mouse Model of Prostatitis

Abstract

Background. Nonbacterial prostatitis has no established etiology. We hypothesized that proteinase-activated receptor-1 (PAR1) can play a role in prostatitis. We therefore investigated the effects of PAR1 stimulation in the context of a new model of murine nonbacterial prostatitis. Methods. Using a hapten (ethanol-dinitrobenzene sulfonic acid- (DNBS-)) induced prostatitis model with both wild-type and PAR1-null mice, we examined (1) the location of PAR1 in the mouse prostate and (2) the impact of a PAR1-activating peptide (TFLLR-NH2: PAR1-TF) on ethanol-DNBS-induced inflammation. Results. Ethanol-DNBS-induced inflammation was maximal at 2 days. In the tissue, PAR1 was expressed predominantly along the apical acini of prostatic epithelium. Although PAR1-TF on its own did not cause inflammation, its coadministration with ethanol-DNBS reduced all indices of acute prostatitis. Further, PAR1-TF administration doubled the prostatic production of interleukin-10 (IL-10) compared with ethanol-DNBS treatment alone. This enhanced IL-10 was not observed in PAR1-null mice and was not caused by the reverse-sequence receptor-inactive peptide, RLLFT-NH2. Surprisingly, PAR1-TF, also diminished ethanol-DNBS-induced inflammation in PAR1-null mice. Conclusions. PAR1 is expressed in the mouse prostate and its activation by PAR1-TF elicits immunomodulatory effects during ethanol-DNBS-induced prostatitis. However, PAR1-TF also diminishes ethanol-DNBS-induced inflammation via a non-PAR1 mechanism by activating an as-yet unknown receptor.

Preclinical models and evaluation criteria of prostatitis

“…Therefore, the prostate tissue is subsequently damaged, resulting in prostatitis. Specific antigens include male accessory gland (MAG) homogenate (prostate, seminal vesicles, and coagulating glands) ( 35 , 49 – 59 ), prostate extract ( 36 , 60 – 63 ), peptide T2 ( 64 – 66 ), rat prostatic steroid-binding proteins(PSBP) ( 35 , 59 , 61 , 67 – 69 ), prostatic acid phosphatase(PAP) ( 70 ), ethanol plus dinitrobenzene sulfonic acid (DNBS) ( 71 , 72 ), MBP-SVS2 or MBP ( 73 ) or prostate-specific proteins p25 ( 74 ). To increase the likelihood of prostatitis, adjuvants that boost the immune response are often used, such as CFA, aluminum hydroxide adjuvant, and liposomes.…”

“…Mice were more susceptible to EAP models than rats, including nonobese diabetic (NOD) ( 35 , 36 , 56 , 58 , 59 , 68 , 69 , 76 ), C57BL/6 ( 56 , 63 , 65 , 66 , 72 , 73 ), C57bl/6 lpr, SJL, AJ ( 63 ), NZB, SWR ( 36 ), BALB/c ( 36 , 63 , 69 ) and SWXJ (H-2q, s) ( 74 ). Most of these mice have autoimmune susceptibility.…”

“…Macroscopic analysis is intuitive, simple, and convenient for grossly morphologically estimate the situation of inflammation within the prostates. After dissection, gross morphological analysis of infected prostates is observed for obvious signs of inflammation, including edema, congestion, and hyperemia ( 16 , 71 , 72 ).…”

Immunomodulatory effects of the pentapeptide YGSRS on human peripheral-blood mononuclear cells

“…Several types of naturally occurring or synthetic oligopeptides and peptides have been reported to show immunomodulatory and anti-inflammatory activities [1][2][3][4] . Clinically used immunosuppressive drug cyclosporine has a cyclic peptide structure 7 .…”

“…Immunomodulatory and anti-inflammatory activities of several types of naturally occurring or synthetic oligopeptides and peptides have been reported [1][2][3][4] . We have also found that certain types of peptide antibiotics suppress proliferation and several cytokine productions in mitogen-activated human peripheral blood mononuclear cells (PBMCs) 5,6 .…”