TNF-alpha, the great imitator: role of p55 and p75 TNF receptors in hematopoiesis

摘要: The clinical application of tumor necrosis factor-alpha (TNF-alpha) has so far been limited due to the severe adverse effects associated with its systemic use. Recently, two distinct TNF receptors molecular weights 55 kDa (TNFR55) and 75 (TNFR75) have cloned characterized. subsequent development TNF-alpha mutants selective activity on either TNFR55 or TNFR75 suggest that such might maintain therapeutic (anti-tumor) potential wild type TNF-alpha, but exhibit reduced toxicity (proinflammatory effects). In present article we discuss previous studies in vitro vivo hematopoiesis. addition, summarize more recent data from our laboratory as well others, elucidating role a direct bifunctional regulator Specifically, is potent inhibitor clonal growth primitive committed murine human bone marrow progenitors combination multiple cytokines, including granulocyte colony-stimulating factor (G-CSF), CSF-1, erythropoietin (Epo), stem cell (SCF), flt3 ligand (FL). contrast, at low concentrations can synergistically directly enhance mature CD34+ when combined GM-CSF interleukin (IL)-3. Thus, critical determinant whether elicits stimulatory inhibitory effect hematopoietic appears be specific factors which it interacts, rather than maturity targeted progenitor. Furthermore, describe involvement signaling TNF-alpha. Whereas involved most observed responses restricted progenitors. Finally, complexity indirect actions hematopoiesis, applications mutants.