Cytokine Expression Pattern in Benign Prostatic Hyperplasia Infiltrating T Cells and Impact of Lymphocytic Infiltration on Cytokine mRNA Profile in Prostatic Tissue

Abstract

SUMMARY: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 ϭ 10) were isolated, activated (PMA ϩ ionomycin), and analyzed for intracellular reactivity with anti-IFN-␥ and IL-2, -4, -5, -6, -10, and -13, as well as TNF-␣ and -␤ by four-color flow cytometry. Lymphokine release was tested using Th1/Th2 cytokine bead arrays. The amount of IFN-␥ and IL-2, -4, -13, and TGF-␤ mRNA expressed in normal prostate (n ϭ 5) was compared with that in BPH tissue separated into segments with normal histology (n ϭ 5), BPH histology with (n ϭ 10) and without (n ϭ 10) lymphocytic infiltration, and BPH nodules (n ϭ 10). Expression of lymphokine receptors was analyzed by immunohistology, flow cytometry, and RT-PCR. We found that 28 Ϯ 18% of BPH T helper cells were IFN-␥ ϩ /IL-4 Ϫ Th1 cells, 10 Ϯ 2% were IFN-␥ Ϫ /IL-4 ϩ Th2, and 12 Ϯ 6% were IFN-␥ ϩ /IL-4 ϩ 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 Ϯ 15%) was significant (Th1: 12 Ϯ 7%; Th0: 5 Ϯ 4%). Lymphokine release upon stimulation was found in the case of IL-2, IL-5, IFN-␥, and TNF-␣ Ͼ 4 g; of IL-4 Ͼ 2 g; and of IL-10 Ͼ 1 g/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-␥ and the increase in TGF-␤ mRNA expression. Infiltrated BPH specimens with BPH histology expressed significantly more IFN-␥ (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-␥ 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. (Lab Invest 2003, 83:1131-1146.

The influence of α1-antagonist on the expression pattern of TNF receptor family in primary culture of prostate epithelial cells from BPH patients

“…Partin et al 7 have demonstrated that doxazosin treatment resulted in caspase-3 activation within 24 h. Caspase-3 is a crucial enzyme for the executive phase of apoptosis that can be activated after the stimulation of tumor necrosis factor family receptors. Konig et al 26,27 have demonstrated that TNF-a can be one of the key factors in the benign prostate hyperplasia (BPH) pathogenesis. TNF-a induces cell death and cell proliferation within prostate tissues.…”

Antagonists of growth hormone-releasing hormone inhibit proliferation induced by inflammation in prostatic epithelial cells

“…IL-17A is secreted by a subclass of T helper cells (T H 17), linked to autoimmune prostatitis, and stimulates the expression of other cytokines and chemokines such as TNF-α, IL-6, and IL-8 (51,52). An earlier study could not demonstrate stimulatory activity on the proliferation of prostatic epithelial cells at the concentration of 20 ng/mL (53).…”

Antiinflammatory effect of androgen receptor activation in human benign prostatic hyperplasia cells

“…This shift is currently viewed as a counter-regulatory mechanism against inflammation, occurring when the Th1 response becomes dangerous for the host. Indeed, as testosterone lymphocytes progressively accumulate, IL4 and IL13 expression increases, suggesting a shift toward a Th0/Th2 immune response (Steiner et al 2003a). There is also evidence that a loss of tolerance to self-antigens, associated with expansion of Th17 cells and IL17 overexpression, is crucial in BPH development (Steiner et al 2003b).…”