A transitional progenitor stage apparently intermediate between the colony forming unit of granulocyte and macrophage (CFU-GM) has been identified. This progenitor, the pre-CFU-M, is not competent to respond to the colony forming unit of macrophage (M-CSF) as a growth and differentiation factor but can be stimulated by a variety of physiologically important hormones and inflammatory signals to undergo clonal proliferation and differentiation in response to the growth factor. Although increased levels of intracellular cAMP are compatible with stimulated transition of the pre-CFU-M to M-CSF competence, activators of adenylate cyclase including E series prostaglandins, isoproterenol, interleukin-1 and forskolin cannot act to stimulate this transition. The potent inflammatory peptide bradykinin and its amino terminal tetrapeptide fragment Arg-Pro-Pro-Gly act in culture to promote sensitivity of the pre-CFU-M to adenylate cyclase activators as stimulants for transition to M-CSF competence. The objectives of this investigation are to further investigate the significance of the transitional pre-CFU-M with regard to inflammatory myelopoiesis and to further explore the regulatory influences of bradykinin in this process. The proposal has five specific aims: 1) to establish the positional status of the pre-CFU-M in the myelopoietic/monocytopoietic pathway; 2) to determine if the transitional process is unique to the pre-CFU-M or is shared by similar progenitors in transition to granulocyte lineage commitment and G-CSF competence; 3) to develop or identify a cell or cell-line model amenable for investigation of bradykinin effects that influence adenylate cyclase activation and transition to M-CSF competence; 4) to determine if bradykinin and Arg-Pro-Pro-Gly can influence functional activities of mature phagocytes and responsiveness of these cells to adenylate cyclase activators; 5) to determine if Arg-Pro-Pro-Gly and bradykinin act through a previously described receptor.
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