Angiogenic activities of interleukin-8, vascular endothelial growth factor and matrix metalloproteinase-9 in breast cancer.

Angiogenesis is a major contributor to tumor growth and metastasis within breast cancer tumor microenvironment in which different proangiogenic factors have been identified and associated with tumor progression, metastasis and poor prognosis. The aim of the current study was to evaluate the angiogenesis among breast cancer patients through ex vivo assessment of the angiogenic factors interleukin 8 (IL-8) and vascular endothelial growth factor (VEGF)-A expressions in excised tumor tissues as well as matrix metalloproteinase 9 (MMP-9) serum levels as well as the prognostic value of MMP-9. Our study included 28 invasive ductal carcinoma female patients who were scheduled for modified radical mastectomy at Medical Research Institute, Alexandria University, Egypt and 10 control subjects. Both IL-8 and VEGF-A expressions were immunohistochemically detected in tumor tissues and serum MMP-9 was determined by ELISA. Although no significant correlations were found between each of IL-8, VEGF-A, MMP-9 levels, and patients' clinicopathological parameters, a significant positive correlation was found between these angiogenic factors each other suggesting their synergistic roles in proceeding angiogenesis. Higher serum MMP-9 level was detected in breast cancer patients compared to the control group, indicating that it can be used as a prognostic biomarker in breast cancer patients.

Immunotherapeutic Approach to Breast Cancer: The Anti-Tumor Effect of Anti-IL-6 Monoclonal Antibodies in Malignant Mammary Tumor Implanted-Mice.

It has been established that suppression of apoptosis during carcinogenesis is the main cause of development and progression of breast cancer. Breast cancer patients have higher circulating levels of IL-6 protecting cancer cells from apoptosis and positively correlated with poor prognosis of the disease. The current work is carried out to fulfill one of our in vivo preclinical studies' for approaching a novel breast cancer immunotherapy through induction of tumor cell apoptosis. The study aims at investigating the potential of anti-IL-6 monoclonal antibodies (mAbs) to suppress IL-6 anti-apoptotic activities in tumor microenvironment of malignant mammary tumor implanted-mice. To achieve this goal, 4 groups of mice were used, group I: served as control, group II: mice implanted with Ehrlich ascites carcinoma cell lines (EAC), through intramuscular injection till tumor inoculation, group III: injected intratumorally with10 µl saline for 3 successive days, and group IV: mice were injected intratumorally one day after tumor inoculation with a dose of 1.5 mg / kg of recombinent anti-IL-6 monoclonal antibodies in10 µl saline for 3 successive days. Apoptosis was evaluated in tumor samples from anti-IL-6 treated tumor implanted mice and compared with controls. Levels of apoptosis in tumor tissue samples of tumor implanted mice treated with anti-IL-6 were significantly (P=0.009) higher than untreated ones. In conclusion, anti-IL-6 monoclonal antibodies have the potential to suppress the anti-apoptotic effect of interleukin-6 (IL-6) within the tumor microenvironment of tumor implanted in mice.

Effects of chronic ethanol and vitamin C administration on production of tumor necrosis factor-alpha and interleukin-6 in rats.

Chronic alcoholism complicated by alcoholic liver disease (ALD) is characterized by activation of inflammatory responses. Alcohol intake increases gut permeability allowing substances such as lipopolysaccharides (LPS) which are strong inducers of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) to enter the circulation. Vitamin C is an antioxidant with many cellular activities seemed to protect cells against alcohol-induced peroxidation. In present study, serum levels of TNF-alpha and IL-6 were measured by ELISA method in four groups of albino rats, each group consists of 10 rats. Group (I) was untreated group (control), group (II) was treated with ethanol, group (III) was treated with ascorbic acid and group (IV) was treated with ethanol + ascorbic acid. Results revealed that both TNF-alpha and IL-6 serum levels were very highly significantly increased in group (II) and (IV) than control group (1) (P < 0.001). Group (III) showed significantly (P < 0.001) decreased TNF-alpha serum level than group (II) and (IV) while it showed significantly (P < 0.001) increased IL-6 serum level than control group (I) and also significantly decreased IL-6 serum level than group (IV). Serum IL-6 level was significantly (P < 0.01) decreased in group (III) than (II). These results indicate that serum levels of the proinflammatory cytokines TNF-alpha and IL-6 may serve as predictive biomarkers for progression of ALD. In addition, using TNF-alpha neutralizing agent (or its antagonist)/or IL-6 as an anti-apoptotic factor could be useful as a treatment strategy of ALD.

Interleukin-2 regulatory effect on P-selectin and interleukin-8 production in patients with chronic renal failure.

Patients with chronic renal failure (CRF) show a clinical state of immunodysfunction that occurs in both humoral and cellular immunity as well as inflammatory response. In this study, we investigated the mononuclear-endothelial cells (MCs/ECs) interaction and the possible protective role of IL-2 as the main T lymphocyte activator in CRF patients. The levels of soluble P-selectin (sP-selectin) and interleukin-8 (IL-8) as the two main mediators of MCs/ECs interaction were measured in IL-2 supplemented and non-supplemented peripheral blood mononuclear cells (PBMCs) supernatant of CRF patients. The obtained results were correlated with those of sex and age matched controls. Significantly higher levels of sP-selectin and IL-8 were detected in both IL-2 supplemented and non-supplemented PBMCs culture supernatant of CRF patients than controls (P = 0.000). Those levels were significantly lower in IL-2 supplemented PBMCs culture supernatant than non-supplemented ones of both CRF (P = 0.000) (for both mediators) and normal control groups (P = 0.01, P= 0.04 for sP-selectin and IL-8 respectively). The higher sP-selectin in CRF indicates impairment of MCs/ECs interaction that may be resulted from blockade of P-selectin receptors on PBMCs by P-selectin molecules shedded from ECs to plasma and bind to PBMCs in vivo. The elevated IL-8 level in PBMCs of CRF reflect the imbalance of Thl/Th2 ratio and subsequent impairment of cellular immunity in those patients. The lower level of both sP-selectin and IL-8 in IL-2 supplemented PBMCs supernatant than in non-supplemented one seemed to be due to the IL-2 induced proliferation of Th1 lymphocytes yielding newly in vitro formed T cells which do not carry P-selectin as well as relative increase of Th1/Th2 ratio in both normal and CRF groups. Thus, IL-2 may improve the MCs/ECs interaction and correct the Th1/Th2 ratio in CRF providing a novel promising therapeutic approach to improve the immuno-pathological condition of those patients.

Study of P53 in peripheral blood and synovial mononuclear cells of rheumatoid arthritis and osteoarthritis patients and its relation to the degree of disease activity.

Over expression of P53 has been described in many inflammatory conditions including rheumatoid arthritis (RA) and osteoarthritis (OA) as a protective mechanism to induce apoptosis of synovial cells. Lack of P53 function through mutation in human synoviocytes increases the development of normal synovial fibroblasts into transformed aggressive synovial fibroblasts. P53 levels were determined in supernatant of cultured mononuclear cells (MCs) isolated from peripheral blood (PBMCs) of patients with RA (n = 10) and OA (n = 10) as well as 10 normal healthy controls (C). P53 levels were also determined in supernatants of MCs isolated from synovial fluid (SFMCs) of RA and OA patients. Results of this work revealed that P53 level was significantly higher in PBMCs supernatant of RA group than those of both (C) and (OA) groups (P = 0.022). P53 level was non-significantly higher in SFMCs supernatant of RA than OA group. Significantly higher levels of P53 was detected in SFMCs culture supernatant than that of PBMCs within each RA (P = 0.003) and OA (P = 0.001) group. Results also showed a significantly positive correlation between P53 levels (in both PBMCs and SFMCs) and the disease activity score (DAS) in RA group (P = 0.01, P = 0.02 respectively) while insignificantly positive correlations between P53 level (in both PBMCs and SFMCs) and radiological grading of OA group were obtained. These results indicate that mutations and consequent dysfunction of P53 gene may result in chronic inflammation and hyperplasia in RA patients. In conclusion, gene therapy targeting P53-dependent pathway could be a promising therapy for RA and OA diseases.

Antibody profile, interferon-gamma and nutritional status in cryptosporidial infection among school children.

Cryptosporidium parvum is more common in children than in adults. The host responses that induce protective immunity against Cryptosporidium is poorly understood. The present work studied the antibody profile, interferon gamma (IFN-gamma) serum level and nutritional status among infected school children, aged eleven years in a rural school in Abis 8 village. Fecal examination showed nineteen cases only infected with Cryptosporidium and ten children free from parasites (controls). The IgA, IgG and IgM serum levels in infected cases were within normal level, without significant differences as compared to controls. The IgE serum level was significantly high in infected children. The cytokine IFN-gamma was significantly lower in the infected cases as compared to controls. Malnutrition was diagnostic among infected children. It was concluded that malnutrition is the important finding related to Cryptosporidium infection. Malnutrition decreased IFN-gamma the recognized factor in protection from infection and elevated serum IgE level.