The proliferation and differentiation of hematopoietic cells are dependent on the continuous presence of a group of growth factors known as colony-stimulating factors (CSFs). At least three known CSFs, Multi-CSF (IL-3), GM-CSF and M-CSF are involved in this process. Recent studies indicate that the action of CSFs is not restricted to hemopoietic precursor cells but includes the more mature macrophage progenitors, known as macrophage colony-forming cells (M-CFC), outside the bone marrow as well. Additionally, CSFs stimulate several functional aspects of mature macrophages, not related to proliferative activity. Murine alveolar M-CFC represent a unique cell population in that they can be induced by all three types of CSFs, either alone or in combination, to undergo clonal growth in vitro. This observation supports the concept that CSFs also play a key role in the regulation of macrophage production a the local level presumably through a paracrine mechanism. In this applicAtion, we will test this hypothesis and define the roles of CSF's in this process using murine alveolar macropohages as our working model. First, using reciprocal clone transfer experiments we will study the mechanisms in which various CSF's interact in the control of alveolar macrophage proliferation and differentiation and define the roles CSF's have in the generation of macrophage heterogeneity. We will then determine whether subsets of alveolar M-CFC exist and what is the relationship between these cells populations in terms of CSF receptor expression during their differentiation process. CSF- receptor bearing cells will be isolated and analyzed by using specific Anti-receptor antibodies and fluorescence-activated cell sorter (FACS) as well as autoradiography using iodinated CSFs. Next, we will study the ontogency of alveolar M-CFC in mice under both normal and pathologic conditions and determine whether they represent local macrophage progenitor cells with self-renewal potential. Finally, we will study the in vivo effect of recombinant CSFs as well as interleukin 1 (IL-1) on the production of alveolar macrophAges and local progenitor cells in both normal and irradiated or chemotherapy treated mice. The effect of CSFs in the regulation of functional activity of mature macrophages will also be examined.
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