Defect of tumour necrosis factor-alpha (TNF-alpha) production and TNF-alpha-induced ICAM-1-expression in BRCA1 mutations carriers.
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).


CONCLUSIONS
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.
Zielinski
Christoph C
CC
Clinical Division of Oncology, Department of Medicine I, University Hospital, Vienna, Austria. christoph.zielinski@akh-wien.ac.at
Budinsky
Alexandra C
AC
Wagner
Teresa M U
TM
Wolfram
Roswitha M
RM
Köstler
Wolfgang J
WJ
Kubista
Marion
M
Brodowicz
Thomas
T
Kubista
Ernst
E
Wiltschke
Christoph
C
D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism*
D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1