GCA patients with a strong systemic inflammatory response, who have been previously shown to be more resistant to corticosteroid therapy, have elevated tissue expression of proinflammatory cytokines IL-1beta, TNFalpha and IL-6. High production of TNFalpha is associated with longer corticosteroid requirements.

Capsaicin, the pungent ingredient of hot chilli pepper, has been recently shown to induce apoptosis in several cell lines through a not well known mechanism. Here, we investigated the role of the vanilloid capsaicin in the death regulation of the human cancer androgen-resistant cell line PC-3. Capsaicin inhibited the growth of PC-3 with an IC(50) of 20 microM cells and induced cell apoptosis, as assessed by flow cytometry and nuclei staining with DAPI. Capsaicin induced apoptosis in prostate cells by a mechanism involving reactive oxygen species generation, dissipation of the mitochondrial inner transmembrane potential (DeltaPsi(m)) and activation of caspase 3. Capsaicin-induced apoptosis was not reduced by the antagonist capsazepine in a dose range from 0.1 microM to 20 microM, suggesting a receptor-independent mechanism. To study the in vivo effects of capsaicinoids, PC-3 cells were grown as xenografts in nude mice. Subcutaneous injection of either capsaicin or capsazepine (5 mg/kg body weight) in nude mice suppressed PC-3 tumor growth in all tumors investigated and induced apoptosis of tumor cells. Our data show a role for capsaicin against androgen-independent prostate cancer cells in vitro and in vivo and suggest that capsaicin is a promising anti-tumor agent in hormone-refractory prostate cancer, which shows resistance to many chemotherapeutic agents.

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Background— Patients with giant-cell arteritis (GCA) who develop a strong acute-phase response are at low risk of disease-related ischemic events. Methods and Results— To assess the potential protective role of proinflammatory cytokines in the development of ischemic events in GCA, we measured tissue expression (66 individuals) and/or circulating levels (80 individuals) of interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), and IL-6 in patients with biopsy-proven GCA. Tissue expression was determined by quantitative real-time polymerase chain reaction and immunohistochemistry. Circulating cytokines were determined by enzyme-linked immunoassay. We found that patients with disease-related ischemic events had lower IL-6 mRNA levels (5.9±2.1 versus 27.6±7.8 relative units, P =0.013), lower IL-6 immunohistochemical expression scores (1.5±0.9 versus 2.7±1, P =0.001), and lower circulating levels of IL-6 (13.6±2.1 versus 24±2.4 pg/mL, P =0.002) than patients without ischemic complications. No significant differences were found for either IL-1β or TNF-α. We subsequently investigated direct effects of IL-6 on vessel wall components. We found that IL-6 stimulates endothelial cell proliferation and differentiation into capillary-like structures and induces full angiogenic activity in both ex vivo (aortic ring) and in vivo (chick chorioallantoic membrane) assays. Conclusions— GCA patients with ischemic complications have lower tissue expression and circulating levels of IL-6 than patients with no ischemic events. IL-6 has relevant direct effects on vascular wall components that might be protective: IL-6 activates a functional program related to angiogenesis that may compensate for ischemia in patients with GCA.

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Vascular inflammation in giant cell arteritis is generally described as a process involving dendritic cells, T-lymphocytes, and effector tissue macrophages. Less is known about the contribution of phagocytes that are recruited early, such as monocytes and neutrophils. These cells express and secrete pro-inflammatory S100 proteins which directly activate endothelial cells. In this study the expression of S100A8/S100A9 and S100A12, pro-inflammatory proteins specific for early recruited phagocytes, was studied in biopsies from 36 patients with giant cell arteritis. In addition, serum concentrations of these proteins were analysed in serum samples from 42 patients and 35 healthy controls. The S100A8/S100A9 complex was found to be abundant in the adventitia and media in affected arteries. Besides neutrophils, cells expressing these proteins belonged to a pro-inflammatory subtype of CD68-positive monocytes. In contrast, S100A12 expression was restricted to neutrophils that were found around the vasa vasorum within the adventitial layer. Both S100A8/S100A9 and S100A12 serum concentrations were significantly higher in patients with giant cell arteritis than in healthy controls. In conclusion, recently recruited phagocytes expressing pro-inflammatory S100 proteins take part in the vascular inflammation of giant cell arteritis. They may play important roles at the vasa vasorum of affected vessels, which represent sites of entry for recruited inflammatory cells. These data indicate that phagocytes within the adventitia and media contribute to the process of inflammation via release of the pro-inflammatory S100 proteins S100A8, S100A9, and S100A12.

It has been recently shown that cannabinoids may regulate the growth of many cell types. In the present work we examined the e¡ect of the anandamide analogue (R)-methanandamide (MET) on androgen-dependent prostate LNCaP cell growth. We found that 0.1 W WM MET had a mitogenic e¡ect measured by [3 H]thymidine incorporation into DNA. The e¡ect exerted by MET was blocked by the cannabinoid receptor antagonists SR141716 (SR1) and SR144528 (SR2) as well as by the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, suggesting an involvement of cannabinoid receptors and the PI3K pathway in the mechanism of MET action. MET treatment of LNCaP cells also induced an up-regulation of androgen receptor expression that was blocked by the two cannabinoid receptor antagonists SR1 and SR2. These results show for the ¢rst time that cannabinoids may modify androgen receptor expression in an androgen-dependent cell line and by this mechanism could regulate prostate cell growth.