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Resveratrol (RSV), the primary polyphenol found in grapes, has been revealed to have anti-inflammatory properties by reducing the capacity of the peripheral blood mononuclear cells to produce pro-inflammatory cytokines, including IL-1ß, IL-6, IL-1ra and TNFα. Considering the close association between chronic inflammation and cancer development, RSV's immunomodulatory properties are one way by which the polyphenol may inhibit cancer initiation, proliferation, neovascularization, and migration. Resveratrol influences the generation of microtumor environment which is one of the key factors in cancer progress. In addition to immunomodulation, RSV inhibits cancer development by expressing anti-oxidant effects, causing cell cycle arrest, stimulating the function of certain enzymes, and activating cell signaling pathways. The end outcome is one of the various forms of cell death, including apoptosis, pyroptosis, necroptosis, and more, as it has been observed in vitro. RSV has been shown to act against cancer in practically every organ, while its effects on colon cancer have been documented more frequently. It is remarkable that longer-term clinical studies that may have established the potential for this natural substance to serve as a therapeutic adjuvant to traditional anti-cancer medications were not prompted by the encouraging outcomes seen with cancer cells treated with non-toxic doses of resveratrol. The current review aims to assess the recent findings about the immunological and anti-cancer characteristics of RSV, with a particular emphasis on cancers of the digestive tract, as a challenge for future clinical research that may contribute to the better prognosis of cancer.

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Introduction: B-cell chronic lymphocytic leukemia (B-CLL) is a common form of leukemia affecting mostly elderly individuals. The course of the disease is usually unremarkable, but because it may proceed with impaired immune defense, B-CLL might be complicated with infections and even death. The leukemic microenvironment containing a number of immune cells, mainly lymphocytes and macrophages capable to produce various molecules including inflammatory cytokines, plays an important role in the development and outcome of the disease. We studied the capacity of Epstein-Barr virus (EBV)-transformed B-cell chronic lymphocytic leukemia (B-CLL) cell line (EHEB) cells, an EBV-transformed line established from a B-CLL patient, to affect the production of inflammatory cytokines by human peripheral blood mononuclear cells (PBMC). Methods: PBMC isolated from peripheral blood of healthy donors were incubated either with EHEB cells or with their supernatants and the production of the following cytokines: tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, interferon (IFN)-γ, IL-1ra, and IL-10 were detected using the enzyme-linked immunosorbent assay method. Results: Direct contact of PBMC incubated with EHEB cells induced a marked increase of TNFα, IL-1ß, IL-6, IFNγ, and IL-10 release by the immune cells. Yet, incubation of PBMC with EHEB cells' supernatant resulted in a mild production of the same cytokines. Conclusions: The noticeable increased production of inflammatory cytokines by PBMC following direct contact with EHEB cells and to a lesser degree with their supernatants implies the existence of an immune dialogue between these two types of cells. The results support the concept that not only leukemic cells, but also peripheral blood mononuclears could serve as a therapeutic target for B-CLL.

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The study was designed to examine the immunomodulatory effect of three commercial sweeteners on human peripheral blood mononuclear cells (PBMC) and on the immune dialogue between these and human HT-29 and HuCC colon cancer lines. PBMC were incubated with Sweet'N Low, Splenda and Stevia and the cytokine production was examined. The cytokine release of PBMC co-cultured with colon cancer cells in the presence of sweeteners was evaluated. Sweet'N Low enhanced IFNγ, IL-1ß and IL-6 release, and augmented HuCC-induced IL-10 secretion. Splenda reduced IFNγ and TNFα secretion by LPS and HuCC stimulated PBMC and enhanced HuCC-induced IL-10 and IL-1ra production. Stevia reduced IL-1ß, TNFα and IL-1ra secretion prompted by HuCC and HT-29 cells and enhanced IL-6 production induced by HuCC. The inhibition of pro-inflammatory- and increased anti-inflammatory cytokines release by Splenda and Stevia indicate that they possess valuable potential as carcinopreventive agents.

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The favourable properties of broccoli on human health are due to their abundant content of vitamins, minerals and isothiocyanates, the sulforaphane (SFN) being the most important. SFN is created from its precursor glucoraphanin and it is released by myrosinase enzymes produced during crushing of the plant. SFN has been shown to possess anti-inflammatory and anticancer properties. The aim of the study was to determine if SFN may affect the immune dialogue between human peripheral blood mononuclear cells (PBMCs) and HT-29 and RKO human colon cancer cells lines. Non- or mitogen-stimulated PBMCs were incubated with various concentrations of SFN, and the secretion of TNFα, IL-1ß, IL-6, IFNγ, IL-2, IL-10 and IL-1ra was determined. In addition, the effect of SFN on the production of these cytokines by PBMCs co-cultured with colon carcinoma cells was examined. SFN exerted a concentration-dependent inhibitory effect on the inflammatory cytokine production by the immune cells. The impact of SFN on the interaction between immune and colon cancer cells underscores its capacity for cancer prevention and development.

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Human health is tightly connected with a great number of gut microbial cells designated as microbiome or microbiota. We have examined the effect of six microbial strains (MS) included in a commercial probiotic on cytokine production by human peripheral blood mononuclear cells (PBMC) and on their immune dialog with colon carcinoma cells. Non-stimulated and lipopolysaccharide (LPS)-stimulated PBMC were incubated for 24 h with MS. The secretion of tumor necrosis factor alpha (TNFα), IL-1ß, IL-6, interferon gamma, IL-10 and IL-1ra and the effect of MS on the immune interplay between PBMC and cells from HT-29 and RKO colon carcinoma lines were evaluated. MS incubated with non-stimulated PBMC induced high expression of all cytokines examined, whereas in those stimulated by LPS, variability in the results was observed. MS added to PBMC co-cultivated with HT-29 or RKO colon cancer cells resulted in downregulation of most cytokines except IL-6 and TNFα, and enhanced production of TNFα and IL-1ß. The MS incorporated in the probiotic affected PBMC' cytokine production and altered the cross-talk between immune and colon cancer cells. The results may clarify the way by which probiotics modify the intestinal environment resulting in a decline of colon cancer development.

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BACKGROUND: Capsaicin, the pungent alkaloid of the chili peppers, has gained a worldwide reputation. In addition to its culinary assets, capsaicin possesses analgesic, anti-inflammatory, antimicrobial, and even carcinopreventive properties. Considering the linkage between chronic inflammation and tumorigenesis, the aim of the study was to evaluate the role of capsaicin in the immune interplay between human peripheral blood mononuclear cells (PBMCs) and HT-29 or RKO cells from human colon carcinoma lines. METHODS: PBMCs were incubated for 24 hours with either HT-29 or RKO cells and concentrations of capsaicin ranging between 10 and 200 µM. Subsequently, the generation of the following cytokines was examined: tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, interferon (IFN)-γ, IL-1ra, and IL-10. RESULTS: Capsaicin caused a concentration-dependent inhibition of colon cancer cells proliferation but had no effect on PBMC viability. 200 µM of capsaicin suppressed the production of all cytokines tested. At lower concentrations, the secretion of TNF-α, IL-1ß, IFN-γ, IL-10, and IL-1ra was inhibited concentration-dependently, whereas that of IL-6 was stimulated. CONCLUSIONS: Capsaicin causes a concentration-dependent alteration of the immune balance between PBMC and colon carcinoma cells expressed as an inhibited generation of inflammatory cytokines. These findings indicate the existence of an additional immunomodulatory mechanism by which this alkaloid may prevent tumor development.

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Prompted by findings suggesting immune instability in infantile bilateral striatal necrosis (IBSN), we evaluated levels of proinflammatory (tumor necrosis factor α, interleukin [IL]-1ß, IL-6, interferon [IFN]γ) and anti-inflammatory (IL-10 and IL-1ra) cytokines produced by peripheral blood mononuclear cells (PBMC) from 6 children with IBSN and 11 age-matched controls. Compared to controls, non-stimulated PBMC from the IBSN group produced a significantly lower level of IL-1ra (by 38%; p < 0.001) and significantly lower levels of TNFα, IL-1ß, and IFNγ (by 36% [p < 0.001], 25% [p = 0.06], and 32% [p < 0.02]) under PBMC stimulation. The severe cachexia manifesting shortly after IBSN onset may impair the immunological state, placing patients at risk of death from hyperpyrexia and sepsis.

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BACKGROUND: The ability for engulfment of pathogens and inert particles is the key hallmark of the phagocytic cells. Phagocytes play a significant role in the modulation of local or extended inflammation. Since fever activates a number of factors linked with the immune response it was the goal of this study to examine the in vitro effect of hyperthermia on the phagocytic capacity, the number of phagocytic cells and the viability of human peripheral blood mononuclear cells (PBMC) at 37 and 40°C. METHODS: PBMC were incubated with 0.8 µm polysterene latex beads, for 2 hours at 37 and 40°C. The number of phagocytic cells, and that of latex particles internalized by each individual cell was counted with a light microscope. In addition, the percentage of viable cells and the number of active metabolic cells was evaluated. RESULTS: A temperature of 40°C significantly increased the number of phagocytic cells and the phagocytic index by 41 and 37% respectively, as compared to cells incubated at 37°C. While the number of vital cells (trypan blue test) did not differ statistically at both temperatures, the number of active metabolic cells (XTT test) after 2 h of incubation at 40°C was 17% higher as compared with that at 37°C. However, the number of active metabolic cells after 24 h of incubation at 40°C was 51% lower compared with cells incubated at 37°C. CONCLUSIONS: The increased phagocytic capacity of human peripheral blood monocytes at high temperature further enlightens the immunomodulatory effect of fever in the immune responses during inflammation.

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The "professional phagocytes", i.e. monocytes and macrophages, play an important role as eliminators of pathogens and as essential components of the immune system. It is well established that monocytes induced for phagocytosis by various stimulators, produce cytokines that are closely related to inflammation. Considering the role of inflammation in carcinogenesis and the existence of an immune dialog between mononuclear and cancer cells, the aim of the present work was to examine cytokine production by immune cells stimulated for phagocytosis by latex particles and incubated with cells from HT-29 and RKO human cancer lines. Human peripheral blood mononuclear cells (PBMC) were incubated with various numbers of polysterene latex beads, 0.8µm in diameter and the secretion of the following cytokines: TNF-α, IL-1ß and IL-6, IL-10 and IL-1ra was examined before and after further incubation with cells of the both cancer lines. Phagocytosis of latex beads by PBMC caused an increased production of TNF-α, IL-1ß and IL-10, whereas that of IL-6 declined. PBMC activated by latex beads and co-cultured with cancer cells generated lesser amount of the three pro-inflammatory cytokines TNF-α, IL-1ß and IL-6, while that of the anti-inflammatory IL-10 and IL-1ra remained unchanged. The results indicate that phagocytosis of polystyrene latex beads by human PBMC alters the dialogue between immune and cells of human colon carcinoma lines, an observation that may clarify the role of the immune cells in attenuating inflammation and restraining carcinogenesis.

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The link between chronic inflammation and colorectal cancer has been well established. The events proceeding along tumorigenesis are complicated and involve cells activated at the cancer microenvironment, tumor infiltrating polymorphonuclears, immune cells including lymphocyte subtypes and peripheral blood mononuclear cells (PBMC), as well as tumor-associated macrophages. The immune cells generate inflammatory cytokines, several of them playing a crucial role in tumorigenesis. Additional factors, such as gene expression regulated by cytokines, assembling of tumor growth- and transforming factors, accelerated angiogenesis, delayed apoptosis, contribute all to initiation, development and migration of tumor cells. Oxygen radical species originating from the inflammatory area promote cell mutation and cancer proliferation. Tumor cells may over-express pro-inflammatory mediators that in turn activate immune cells for inflammatory cytokines production. Consequently, an immune dialogue emerges between immune and cancer cells orchestrated through a number of activated molecular pathways. Cytokines, encompassing migration inhibitory factor, transforming growth factor beta 1, tumor necrosis factor-α, Interleukin (IL)-6, IL-10, IL-12, IL-17, IL-23 have been reported to be involved in human cancer development. Some cytokines, namely IL-5, IL-6, IL-10, IL-22 and growth factors promote tumor development and metastasis, and inhibit apoptosis via activation of signal transducer activator transcription-3 transcription factor. Colon cancer environment comprises mesenchymal, endothelial and immune cells. Assessment of the interaction between components in the tumor environment and malignant cells requires a reconsideration of a few topics elucidating the role of chronic inflammation in carcinogenesis, the function of the immune cells expressed by inflammatory cytokine production, the immunomodulation of cancer cells and the existence of a cross-talk between immune and malignant cells leading to a balance in cytokine production. It is conceivable that the prevalence of anti-inflammatory cytokine production by PBMC in the affected colonic mucosa will contribute to the delay, or even to halt down malignant expansion. Targeting the interplay between immune and cancer cells by mediators capable to alter cytokine secretion toward increased anti-inflammatory cytokine release by PBMC and tumor associated macrophages, may serve as an additional strategy for treatment of malignant diseases. This review will focus on the inflammatory events preceding tumorigenesis in general, and on a number of modulators capable to affect colon cancer cell-induced production of inflammatory cytokines by PBMC through alteration of the immune cross-talk between PBMC and cancer cells.

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The aim of the study was to examine the effect of androgen deprivation drugs, i.e. leuprolide and bicalutamide on the immune cross-talk between human peripheral blood mononuclear cells (PBMC) and cells from PC-3 and LNCaP human prostate cancer lines. PBMC, PC-3 and LNCaP were separately incubated without and with two androgen-deprivation drugs, i.e. leuprolide and bicalutamide, and the secretion of IL-1ß, IL-6, IL-1ra and IL-10 was examined. In addition, the effect of both drugs on the production of those cytokines was carried out after 24 hours incubation of PBMC with both types of cancer cells. Leuprolide or bicalutamide did not affect the production of the cytokines by PBMC or by the prostate cancer cells from the two lines. Incubation of PBMC with PC-3 or LNCaP cells caused increased production of IL-1ß, IL-6 and IL-10 as compared with PBMC incubated without malignant cells. While 10(-7) M and 10(-8) M of leuprolide caused a decreased secretion of IL-1ß by PBMC previously incubated with prostate cancer cells without the drug, bicalutamide did not affect this PBMC activity at any drug concentration. This observation suggests the existence of an additional mechanism explaining the effect of androgen deprivation therapy in prostate cancer patients.

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OBJECTIVE: To compare the production of pro- and anti-inflammatory cytokines by peripheral blood mononuclear cells (PBMC) from obese but otherwise healthy individuals to that of normal-weight volunteers. METHODS: 25 healthy normal-weight subjects and 41 obese individuals were enrolled. Weight and height were measured twice. PBMC were examined for their capacity to generate pro-inflammatory (TNF-α, IFN-γ, IL-1ß, IL-6, IL-2) and anti-inflammatory IL-10 and IL-1ra) cytokines. RESULTS: PBMC from obese individuals, compared to those from subjects with normal weight showed an increased production of the pro-inflammatory cytokines IL-2 (6.7 ± 0.4. vs. 4.9 ± 0.3 ng/ml; p = 0.003), TNF-α (505 ± 45 vs. 277 ± 32 pg/ml; p = 0.001), and IFN-γ (93.8 ± 6.0 vs. 73.9 ± 2.7 ng/ml; p = 0.0016). However, PBMC from obese individuals produced a lower amount of the anti-inflammatory cytokine IL-10 (651 ±72 pg/ml) versus those from subjects with normal weight (951 ± 133 pg/ml; p = 0.039). CONCLUSIONS: The findings imply that obese individuals are in a 'low-grade inflammatory state', presumed to be connected with metabolic and cardiovascular co morbidities. The surplus of pro-inflammatory cytokines produced by circulating mononuclear cells of obese individuals, together with those secreted by adipocytes and non-fat cells in the adipose tissue, may contribute to the predisposition of obese patients to inflammation and infections.

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Resveratrol, a natural polyphenolic compound found mainly in grapes and their seeds, is gaining a widespread appreciation as a therapeutic adjuvant in a variety of diseases including cancer prevention. We examined the effect of resveratrol as a modulator of the immune dialog between peripheral blood mononuclear cells and those from two human colon carcinoma lines, expressed by a possible alteration of cytokine production. Resveratrol, incubated with non-stimulated mononuclear cells, caused a certain reduction of IL-6, IL-1ra and IL-10, and a moderate increase of TNFα release. On the other hand, resveratrol did not affect cytokine production by cancer cells from both lines. When resveratrol was added to immune and cancer cells jointly, an altered dose-dependent decreased production of the examined cytokines was obtained. These results favor the existence of a mechanism, additional to those already described, that may explain the preventive effect of resveratrol on tumorigenesis.

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Following observations indicating the existence of a relationship between immune and cancer cells in the course of tumor development, it was the aim of the study to establish the role of 1α,25-dihydroxyvitamin D3 (vit. D) in the functional equilibrium between cells from two human colon carcinoma lines-induced cytokine production by peripheral blood mononuclear cells (PBMC). PBMC were incubated with HT-29 and RKO human colon cancer cells with and without vit. D at final concentrations of 10⁻8, 10⁻7 or 10⁻6 M. The production of the cytokines TNF-α, IL-6 and IL-10, as well as the effect of the vitamin on tumor cell proliferation were evaluated. Incubation of PBMC with either HT-29 or RKO cells caused a significant stimulation of both pro- and anti-inflammatory cytokine generation. Addition of vit. D to the incubation mixture containing PBMC and cells of both colon carcinoma lines caused a marked inhibition of the generation of the pro-inflammatory cytokines TNF-α and IL-6 and to a lesser extent-of the IL-10. Vit. D did not affect the proliferation of the cancer cells. The results indicate the existence of a functional "dialog" between immune and cancer cells expressed by an alteration of their capacity for cytokine production and support the role of inflammation in carcinogenesis. The ability of vit. D to attenuate production of the pro-inflammatory cytokines when added to the incubation mixture containing PBMC and cancer cells endorses observations as for the beneficial role of the vitamin in suppressing inflammation with subsequent colon cancer prevention.

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A substantial number of studies provide evidence that inflammation may play a significant role in the pathogenesis of prostate cancer via increased activity of inflammatory cytokines, particularly IL-6. We have previously shown that peripheral blood mononuclear cells (PBMC) are capable of carrying out an in vitro "immunomodulatory dialog" with colon cancer cells expressed by an increased production of pro-inflammatory cytokines by PBMC. The aim of the current study was to examine the model of cell-to-cell interaction between PBMC and prostate cancer cells from two lines - androgen resistant (PC-3) and androgen-dependent (LNCaP). For that purpose, cancer cells from both lines were incubated with PBMC, and cytokine secretion by PBMC was evaluated. The results showed a cell-concentration dependent increase in secretion of the pro-inflammatory cytokine IL-6 by PBMC induced by cells from both lines, whereas generation of IL-1ß and the anti-inflammatory cytokine IL-10 were found to be increased after incubation with PC-3 cells only. The secretion of IL-10 was slightly lower following incubation of PBMC with supernatants derived from PC-3 cells. The results of the study support the possibility that prostate cancer cell-induced cytokine production by PBMC, and particularly IL-6, are involved in prostate cancer development. The discrepancy between the effect of the two prostate cancer cell lines on cytokine secretion by PBMC may be due to their different androgen dependency.

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BACKGROUND: Studies have shown that caffeine might be capable to prevent colon cancer development. This activity is linked in part to its anti-inflammatory properties mediated through modulation of immune responses. It was the aim of the study to evaluate the role of caffeine in the immune balance between peripheral blood mononuclear cells (PBMC) and those of HT-29 and RKO human colon cancer lines. METHODS: Cytokine production was evaluated following incubation of the two types of cancer cells without and with three concentrations of caffeine. RESULTS: A concentration-dependent inhibition of TNFα and IFNγ secretion by PBMC was observed only after their stimulation by cancer cells. Reduction of the anti-inflammatory IL-1ra and IL-10 production was observed using higher caffeine concentrations only. CONCLUSION: We presume that by changing the equilibrium between pro- and anti-inflammatory cytokines in favor of anti-inflammation, caffeine may reduce the inflammatory process with a consequent suppression of colorectal cancer progress.

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The study was designed to examine whether the hydrophilic statin - pravastatin and the hydrophobic statin - simvastatin affect colon cancer cell-induced cytokine secretion by peripheral blood mononuclear cells (PBMC). Statins were added to human colon cancer cells (HT-29 and RKO), or to PBMC incubated separately or jointly. The secretion of the pro-inflammatory cytokines IL-1ß and IFNγ and that of the anti-inflammatory cytokines IL-1ra and IL-10 induced by cancer cells was decreased by simvastatin but not by pravastatin, whereas that of IL-6 was not affected by both drugs. Conditioned media from colon cancer cells incubated with either simvastatin or pravastatin induced stimulation of cytokine production by PBMC similar to that caused by conditioned media derived from cancer cells incubated without the drugs, suggesting that simvastatin acts directly on the interaction between cancer and PBM cells. Simvastatin, but not pravastatin, caused inhibition of both cancer cell proliferation. The results imply that simvastatin may affect inflammation-induced colon cancer proliferation via alteration of the equilibrium between pro- and anti-inflammatory cytokines.

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The effect of aspirin on colon-cancer-cell-induced cytokine secretion by peripheral blood mononuclear cells (PBMC) was examined. Aspirin was added to human colon cancer cells (HT-29 and RKO) or to PBMC incubated separately or jointly. The secretion of IFNγ, IL-6, and IL-10 induced by HT-29 cells was decreased, that of IL-1ß was slightly increased, whereas IL-1ra production was not affected. With RKO cells, aspirin reduced IL-6, IL-1ra, and IL-10 synthesis and enhanced IFNγ secretion, while IL-1ß remained unchanged. Conditioned media from colon cancer cells incubated without or with aspirin stimulated cytokine productions by PBMC similarly, suggesting that aspirin acts on the cell-to-cell interaction between cancer cells and PBMC. The results indicate that aspirin alter the balance between pro- and anti-inflammatory cytokines generated by interaction between colon cancer and immune cells disclosing an additional role of the drug in affecting inflammation-induced colon cancer.

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Patients with ulcerative colitis and Crohn's disease are at increased risk for colorectal cancer, a phenomenon assumed to be at least in part consequence of chronic inflammation. The purpose of this study was to examine whether human colon cancer cells may promote immune cells to produce cytokines, particularly those involved in inflammatory reaction. HT-29 and RKO human colon cancer cell lines were used. Human peripheral blood mononuclear cells (PBMC) were incubated for 24 h without or with cancer cells, or with supernatants derived from these cells cultured at the same conditions. TNFα, IL-1ß, IL-6, IFNγ, IL-1ra and IL-10 secreted by PBMC were detected using specific ELISA kits. Interaction between colon cancer cells and PBMC induced secretion of pro- and anti-inflammatory cytokines in a dose-dependent manner. Furthermore, supernatants from increasing number of colon cancer cells caused a dose-dependent cytokine secretion. However, the production of cytokines was more pronounced when PBMC were directly exposed to tumor cells as compared to their supernatants. The results of our experimental model demonstrating an altered balance between pro- and anti-inflammatory cytokines generated by interaction between colon cancer and immune cells support the role of the malignant cells in promoting inflammation as one of the mechanisms for progression of colon cancer.

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Since both statins and lycopene exert immunomodulatory activities following incubation with human peripheral blood mononuclear cells (PBMC), the present work was designed to examine whether they may induce a synergistic or antagonistic effect on cytokine production while applied together. Peripheral blood mononuclear cells isolated from 15 healthy subjects were incubated for 24 h as follows: (1) without and with 0.125 or 0.25 microM lycopene, (2) without and with 10 or 50 mM pravastatin or simvastatin, and (3) with lycopene and with one of the statins together at the respective doses. The production of the following cytokines was assessed: interleukin (IL)-1beta, IL-1ra, IL-2, and IL-10, as well as tumor necrosis factor alpha (TNFalpha) and interferon gamma (IFNgamma). The results showed that lycopene and simvastatin applied together reduced TNFalpha and IFNgamma secretion, and abolished the increased production of the proinflammatory cytokine IL-1gamma caused by incubation with simvastatin only, an observation suggesting that simultaneous administration of both substances may reduce inflammatory responses.

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