INHIBITION OF STEM-CELL FACTOR-INDUCED PROLIFERATION OF PRIMITIVE MURINE HEMATOPOIETIC PROGENITOR CELLS SIGNALED THROUGH THE 75-KILODALTON TUMOR-NECROSIS-FACTOR RECEPTOR - REGULATION OF C-KIT AND P53 EXPRESSION

TNF-alpha is a pleiotropic cytokine with stimulatory as well as inhibi tory effects on hematopoiesis. We have previously demonstrated that TN F-alpha directly inhibits CSF-induced proliferation of primitive murin e lineage-negative bone marrow progenitors (Lin(-)) and stem cell anti gen-1 hematopoietic progenitors through the 75-kDa TNF receptor (TNF-R 2), whereas TNF-alpha-induced inhibition of more committed Lin(-) prog enitors is mediated through the 55-kDa TNF-R (TNF-R1), indicating a di fferential role of the two TNF-Rs in hematopoiesis. Numerous studies h ave demonstrated the ability of stem cell factor (SCF), a key regulato r of hematopoiesis signaling through c-kit, to synergize with other he matopoietic growth factors, but little is known about cytokines capabl e of inhibiting hematopoiesis induced by SCF. While TNF-alpha has been demonstrated to enhance SCF-induced proliferation of myeloid leukemia blasts, the present report demonstrates that TNF-alpha, by signaling through TNF-R2, inhibits SCF-induced proliferation of normal murine Li n(-) and stem cell antigen-1 hematopoietic progenitors. SCF-stimulated proliferation of the hematopoietic cell line FDC-P1 was also potently inhibited by TNF-alpha and was accompanied by down-regulation of c-ki t cell surface expression as well as c-kit mRNA levels. Finally, treat ment of the FDC-P1 cell line with TNF-alpha resulted in increased leve ls of the tumor suppressor p53 mRNA, suggesting another mechanism by w hich hematopoietic effects of TNF-alpha may be mediated.