The interleukin-1 family of cytokines and receptors in human breast cancer: implications for tumor progression.

We have previously described the expression of interleukin cytokines (IL)-1alpha, IL-1beta, and IL-1 receptor antagonist (IL-1ra) in human breast cancer (HBC) tissue. Based on our previous studies, we hypothesize that the IL-1 family of cytokines, antagonists (IL-1ra) and receptors (IL-1RI and IL-1RII) are present within the human breast cancer (HBC) tumor microenvironment and that the IL-1 network of cytokines and receptors within the tumor microenvironment can control tumor cell subpopulation expression of other protumorigenic cytokines such as the angiogenic/growth factor, interleukin-8 (IL-8). To test this hypothesis we characterized the in vivo expression of the IL-1 network in HBC tissues and homogenates by immunohistochemistry (IHC) and ELISA. Additionally, we examined IL-1R expression in HBC cell lines in vitro and in a murine xenograft model by IHC. Finally, we determined the ability of IL-1 to induce IL-8 expression in in vitro using HBC cell lines. We observed that not only are the IL-1 cytokines present in HBC tissue and homogenates, but that IL-1Rs and IL-8 are also present in the HBC tumor microenvironment. Additionally, expression levels for some members of the IL-1/IL-8 network of cytokines correlated with the prognostic indicators, ER/PR. Using HBC cell lines, we observed that HBC cell lines express IL-1Rs in vitro and in the xenograft model. Furthermore, in vitro, HBC cell lines show a spectrum of responsiveness to IL-1 as measured by expression the proangiogenic/mitogenic cytokine IL-8. Our data clearly demonstrate the presence and distribution of IL-1 cytokines and receptors in HBC and suggests that the local expression of IL-1 results in the activation of a population of cells within the HBC tumor microenvironment. This activation of the IL-1/IL-1R cytokine family via autocrine and/or paracrine mechanisms leads to a cascade of secondary protumorigenic cytokines. These secondary signals induce the expression of numerous protumorigenic activities such as the expression of IL-8, and subsequently contribute to angiogenesis, tumor proliferation, and tumor invasion.

In vitro demonstration of breast cancer tumor cell sub-populations based on interleukin-1/tumor necrosis factor induction of interleukin-8 expression.

Interleukin-8 (IL-8) has been identified as an angiogenesis factor (AF) as well as a tumor cell chemotactic factor and mitogen. Recent in vivo studies have demonstrated the expression of IL-8, IL-1 and TNF, as well their receptors, on various sub-populations of tumor cells in human breast cancer (HBC). Since pro-inflammatory cytokines such as IL-1 and TNF are known inducers of IL-8 in non-tumor cells, we hypothesize that IL-1/TNF may act as an IL-8 inducer in HBC, and thus enhance HBC tumor progression. To begin to test this hypothesis, we evaluated the ability of: a) human breast cancer cell lines (BCC) and normal human breast epithelial cell lines (BEC) to produce IL-8 in vitro; and b) IL-1 and TNF to regulate the expression of IL-8. In general, basal IL-8 expression was low in all 8 cell lines examined. TNF-alpha and TNF-beta induced a 3- to 24-fold increase in IL-8 protein expression of BEC, and a 2- to 8-fold increased IL-8 expression in estrogen-independent BCC cell lines and no significant IL-8 expression in estrogen-dependent cell lines. Conversely, IL-1alpha and IL-1beta, induced a 5- to 104-fold stimulation of BEC and a 330 to 1,138-fold increase in IL-8 expression in estrogen independent BCC. These observations demonstrate the ability of HBC cells to produce IL-8 in vitro and further indicate that IL-1 is a potent inducer of IL-8 expression by BEC and BCC. Furthermore, this in vitro data support the hypothesis, that within the HBC tumor microenvironment, tumor cells exist that respond to pro-inflammatory cytokine (IL-1) stimulation (i.e. MDA-MB-231) and those that do not (i.e. MCF-7). Additionally, HBC tumor cell lines that can be induced to express high levels of IL-8 tend to be associated with a more aggressive phenotype.

Nerve growth factor and chronic prostatitis/chronic pelvic pain syndrome.

OBJECTIVES: To investigate whether the pain experienced by patients with chronic prostatitis/chronic pelvic pain syndrome (CPPS) may be related to the expression of nerve growth factor (NGF), induced by inflammation and tissue injury experienced as a result of chronic inflammation. CPPS is a disease of unknown pathogenesis. METHODS: We measured the levels of NGF and the pro-inflammatory cytokine interleukin (IL)-6 and compared these with the levels of IL-8, interferon-gamma, IL-2, and IL-10 in the seminal plasma of 31 patients with CPPS and 14 controls using enzyme-linked immunosorbent assay technology. Results were correlated with health-related quality of life as measured by the multidimensional pain inventory, the McGill pain questionnaire, and the International Prostate Symptom Score. RESULTS: The cytokines analyzed were detectable in the seminal plasma from the patients with CPPS and controls. NGF correlated directly with pain severity (P <0.01) and IL-10 levels (P <0.04), and IL-6 correlated inversely with pain severity (P <0.03). CONCLUSIONS: These results suggest that NGF and cytokines that regulate inflammation (IL-6 and IL-10) may play a role in the pain symptoms experienced by patients with CPPS.

Interleukin-10 levels in seminal plasma: implications for chronic prostatitis-chronic pelvic pain syndrome.

PURPOSE: Chronic prostatitis-chronic pelvic pain syndrome is a disease of unknown pathogenesis. We investigated whether the chronic inflammation and pain experienced by patients may be caused by an imbalance of proinflammatory versus anti-inflammatory cytokines within the prostate, namely interleukin (IL)-8, interferon-gamma and IL-2 versus IL-10. We measured these inflammatory cytokines in seminal plasma as a reflection of the prostate environment. MATERIALS AND METHODS: We measured levels of IL-8, interferon-gamma, IL-2 and IL-10 in the seminal plasma of 31 patients with chronic prostatitis-chronic pelvic pain syndrome and 14 controls using enzyme-linked immunosorbent assay. Results were correlated with health related quality of life, as measured by the Multidimensional Pain Inventory, McGill pain questionnaire and International Prostate Symptom Score. RESULTS: The cytokines analyzed were detectable in the seminal plasma of patients with chronic prostatitis-chronic pelvic pain syndrome and controls. Interferon-gamma, IL-2 and IL-10 levels were statistically greater in patients. Furthermore, IL-10 levels correlated directly with measures of life interference (r = 0.52, p <0.01) and pain severity (r = 0.53, p <0 0.01), and inversely with spousal support (r = -0.39, p <0.04). CONCLUSIONS: Our study suggests that IL-10 may have a role in the pain symptoms experienced by patients with chronic prostatitis-chronic pelvic pain syndrome.