Defect of Tumour Necrosis Factor-α (TNF-α) Production and TNF-α-induced ICAM-1 – Expression in BRCA1 Mutations Carriers

Autor: Zielinski, Christoph, Budinsky, Alexandra, Wagner, Teresa, Wolfram, Roswitha, Köstler, Wolfgang, Kubista, Marion, Brodowicz, Thomas, Kubista, Ernst, Wiltschke, Christoph
Zdroj: Breast Cancer Research and Treatment; September 2003, Vol. 81 Issue: 2 p99-105, 7p
Abstrakt: Background. Tumour necrosis factor-α (TNF-α) 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-α 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-α 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-α, as compared to monocytes derived from healthy age-matched control females. In contrast, no difference in LPS- or TNF-α-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-α 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-α and of TNF-α-induced ICAM-1 expression on peripheral blood monocytes.
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