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  • Title: Defect of tumour necrosis factor-alpha (TNF-alpha) production and TNF-alpha-induced ICAM-1-expression in BRCA1 mutations carriers.
    Author: Zielinski CC, Budinsky AC, Wagner TM, Wolfram RM, Köstler WJ, Kubista M, Brodowicz T, Kubista E, Wiltschke C.
    Journal: Breast Cancer Res Treat; 2003 Sep; 81(2):99-105. PubMed ID: 14572152.
    Abstract:
    BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) is a potent cytokine secreted primarily by activated cells from the monocyte/macrophage lineage which exhibits various antitumoral effects including the induction of apoptosis, necrosis, activation of lytic effector cells as well as upregulation of the expression of intercellular adhesion molecule-1 (ICAM-1) which is of decisive importance in the interaction with lymphokine activated killer cells. Previous studies from our laboratory have indicated impaired production of TNF-alpha by monocytes as well as decreased expression of ICAM-1 on monocytes derived from patients with various stages of breast cancer. METHODS: In the present experiments, we have assessed spontaneous as well as lipopolysaccharide (LPS)-induced production of TNF-alpha by as well as expression of ICAM-1 on monocytes derived from healthy females with germline mutations of BRCA1 and from healthy age-matched control females. RESULTS: We report that monocytes derived from healthy women with various germline mutations of BRCA1 had significantly decreased spontaneous (p = 0.03) and LPS-induced (p < 0.001) production of TNF-alpha, as compared to monocytes derived from healthy age-matched control females. In contrast, no difference in LPS- or TNF-alpha-induced production of interleukin-6 was found. Whereas unstimulated monocytes derived from healthy women with germline mutations of BRCA1 and from healthy control women had similar expression of ICAM-1, stimulation with cytokines TNF-alpha and/or interleukin-1 led to a significant increase of ICAM-1 expression on monocytes derived from control females only, but not from BRCA1 germline mutation carriers (p < 0.001). CONCLUSION: We conclude that the presence of germline mutations of BRCA1 was associated with a selective deficiency in spontaneous and LPS-induced production of TNF-alpha and of TNF-alpha-induced ICAM-1 expression on peripheral blood monocytes.
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