Cytokine expression pattern in benign prostatic hyperplasia infiltrating T cells and impact of lymphocytic infiltration on cytokine mRNA profile in prostatic tissue.

The aim of the study is to characterize the type of immune response in benign prostatic hyperplasia (BPH) tissue. BPH tissue-derived T cells (n = 10) were isolated, activated (PMA + ionomycin), and analyzed for intracellular reactivity with anti-IFN-gamma and IL-2, -4, -5, -6, -10, and -13, as well as TNF-alpha and -beta by four-color flow cytometry. Lymphokine release was tested using Th1/Th2 cytokine bead arrays. The amount of IFN-gamma and IL-2, -4, -13, and TGF-beta mRNA expressed in normal prostate (n = 5) was compared with that in BPH tissue separated into segments with normal histology (n = 5), BPH histology with (n = 10) and without (n = 10) lymphocytic infiltration, and BPH nodules (n = 10). Expression of lymphokine receptors was analyzed by immunohistology, flow cytometry, and RT-PCR. We found that 28 +/- 18% of BPH T helper cells were IFN-gamma(+)/IL-4(-) Th1 cells, 10 +/- 2% were IFN-gamma(-)/IL-4(+) Th2, and 12 +/- 6% were IFN-gamma(+)/IL-4(+) Th0 cells. In relation, cytotoxic and double-negative BPH T lymphocytes showed a slight decrease in Th1 and Th0 in favor of Th2. In double-positive BPH T lymphocytes, the trend toward Th2 (35 +/- 15%) was significant (Th1: 12 +/- 7%; Th0: 5 +/- 4%). Lymphokine release upon stimulation was found in the case of IL-2, IL-5, IFN-gamma, and TNF-alpha > 4 microg; of IL-4 > 2 microg; and of IL-10 > 1 microg/ml. Expression of lymphokine mRNA in tissue was increased (2- to 10-fold) in infiltrated BPH specimens with and without BPH histology. The infiltrated BPH specimens with normal histology differed from those with BPH histology, most evident by the significant decrease in IFN-gamma and the increase in TGF-beta mRNA expression. Infiltrated BPH specimens with BPH histology expressed significantly more IFN-gamma (5-fold), IL-2 (10-fold), and IL-13 (2.8-fold) when compared with noninfiltrated BPH specimens. BPH nodules, however, showed the highest level of expression of IL-4 and IL-13, with only intermediate levels of IFN-gamma and very low levels of IL-2 mRNA. Immune response in histologically less transformed BPH specimens is primarily of type 1, whereas in chronically infiltrated nodular BPH and especially within BPH nodules, it is predominantly of type 0 or type 2.

Expression and function of pro-inflammatory interleukin IL-17 and IL-17 receptor in normal, benign hyperplastic, and malignant prostate.

INTRODUCTION AND OBJECTIVES: To investigate factors involved in inflammation of the prostate besides IL-15, we screened prostatic cells and tissues for IL-17 and IL-17 receptor expression. METHODS: Normal prostate (n = 1), BPH (n = 19), and carcinoma (CaP, n = 12) specimens were screened for IL-17, IL-17 receptor, CD45, IL-6, and IL-8 mRNA expression. The carcinoma cell lines DU145, PC3, LNCaP, and BPH-epithelial (EC), stromal cell (SC) preparations, and BPH-T-cell lines were analyzed for IL-17 production by RT-PCR and ELISA. The effect of IL-17 on IL-6, IL-8, TGF-beta1, and fibroblast growth factor (FGF-2) mRNA expression and/or release of SC was analyzed using real-time PCR and/or ELISA. Immunohistochemistry was used to localize both IL-17 and IL-17 receptor. RESULTS: In the normal prostate, IL-17 expression was very weak and restricted to lymphocytes. In 79% of BPH and 58% of CaP specimens, IL-17 mRNA and protein expression was increased. IL-17 mRNA expression could be shown for activated BPH-T-cells and to some extend for BPH-EC. Expression of IL-17 receptor was ubiquitous. Release of IL-17 was shown only for activated BPH-T-cells. IL-17 stimulated expression of IL-6 (13-fold) and IL-8 (26-fold) by prostatic BPH-SC. In situ, however, the amount of IL-17mRNA in BPH-tissue did not correlate with the amount of IL-6 and IL-8 mRNA. In CaP tissue, significant correlation was found only between the amount of IL-6 and IL-8 mRNA. CONCLUSIONS: Activated BPH-T-cells abundantly express IL-17. The increase of IL-17 in BPH-tissues goes hand in hand with elevated levels of IL-15, a pro-inflammatory cytokine with T-cell growth factor properties. A clinical relevance of increased IL-17 expression under pathological conditions is suggested by the demonstration of significant upregulation of IL-6 and IL-8 production of prostatic SC by IL-17.

Increased expression of lymphocyte-derived cytokines in benign hyperplastic prostate tissue, identification of the producing cell types, and effect of differentially expressed cytokines on stromal cell proliferation.

BACKGROUND: Benign prostatic hyperplasia (BPH) frequently exhibit infiltration of CD4 (+)/CD45RO (+) memory-T-lymphocytes. Expression and impact of lymphocyte-derived growth factors on prostatic stromal cell (PSC) growth were investigated. METHODS; Lymphokine synthesis in normal prostate tissues (n = 3), BPH-tissues (n = 13), BPH-derived T-cells (n = 6), BPH-derived epithelial cells (BPH-EC) (n = 5), normal prostate-derived (n = 3) and BPH-derived stromal cell lines (BPH-SC) (n = 6), and prostate cancer (CaP) lines (n = 3) was analyzed by RT-PCR and Southern-blotting. The effect of interleukin (IL)-2, -4, -7, and interferon-gamma (IFN-gamma) on normal and BPH-SC growth was investigated by (3)H-thymidine incorporation assays. RESULTS: All BPH-tissues and, to a lesser degree, normal prostates, expressed significant amounts of IFN-gamma mRNA. However, only BPH-tissues contained IL-2 and IL-4 mRNA (ratio: 10:13). BPH-T-cell lines were heterogeneous in composition and expressed significant amounts of IFN-gamma, IL-2, and IL-4 mRNA. Low level expression of these lymphokines was also observed in BPH-EC, CaP lines, and PSC lines. IL-2, -7 and IFN-gamma stimulated the proliferation of BPH-PSC lines but not that of normal PSC, while IL-4 inhibited BPH-PSC growth. CONCLUSIONS: Chronic inflammation may induce an increased growth pattern of fibromuscular tissue in BPH similar to that of wound healing.