Chronic inflammation and hemodialysis reduce immune competence of peripheral blood leukocytes in end-stage renal failure patients.

Immunoincompetence is a profound problem in end-stage renal failure patients undergoing hemodialysis, and chronic inflammation with altered serum levels of inflammation markers has been reported. Gene expression patterns have had little relevance for leukocyte research so far because of limitations in transcript levels and stability. Using a new stimulation system we induced the expression of immune-relevant transcripts in whole blood preparations ex vivo and stabilized transcript levels by preventing RNA degradation and uncontrolled gene induction. Using quantitative real-time PCR we could show that basal TGF-beta mRNA expression is about 2-fold decreased in end-stage renal failure patients, while expression of TNF-alpha becomes 2-fold increased, further doubling during hemodialysis. By short term stimulation with phytohemagglutinin (PHA) for 2 h we tested for the immune competence of peripheral blood leukocytes and demonstrated that hemodialysis decreases TNF-alpha-mediated immune responsiveness more than 3-fold. This study shows by induction and stabilization of immune-relevant transcripts that chronic inflammation and hemodialysis are crucial factors for disturbed immune competence of end-stage renal failure patients.

Bone metastasis: Osteoblasts affect growth and adhesion regulons in prostate tumor cells and provoke osteomimicry.

Bone metastasis is the primary cause of death in human prostate cancer. Disseminated from primary tumor and distributed via the bloodstream, a proportion of prostate carcinoma cells eventually reach the skeleton and develop into metastases, requiring adhesion to inner bone surfaces lined by osteoblasts. The crosstalk of tumor cells with osteoblasts is a critical but poorly characterized step in the metastatic process. Using an in vitro metastasis model system, we have been examining effects of osteoblast-released factors on gene expression of prostate carcinoma cells. Here, we show by large-scale transcript profiling and quantitative RT-PCR that osteoblast-released factors target in particular the proliferation and adhesion regulons of tumor cells. Genes encoding components of the cell-cycle control machinery and connected pathways are predominantly repressed and cell proliferation is slowed down, resembling in vivo observations assumed to render commonly used chemotherapeutic measures ineffective. Genes encoding anchoring junction components are predominantly elevated, and the adhesion properties of tumor cells are altered. Moreover, prostate carcinoma cells are provoked to undergo osteomimicry, i.e., to express bone cell-related genes. The data indicate that the crosstalk with osteoblasts induces expressional changes in prostate carcinoma cells favoring the bone colonization process.