Regulation of platelet-derived growth factor (PDGF) and alveolar macrophage-derived PDGF by alpha 2-macroglobulin.
In vitro findings suggest that alpha 2M is an important regulator of PDGF-stimulated fibroblast proliferation and chemotaxis. Native alpha 2M binds to PDGF and prevents PDGF from interacting with its receptor, but serves as an extracellular reservoir for the growth factor, which can be released over time in a controlled fashion to interact with the PDGF-alpha or -beta receptor. Methylamine-activated alpha 2M synergistically enhances PDGF-induced cell growth, whereas plasmin-activated alpha 2M inhibits PDGF-stimulated fibroblast proliferation. The reason for the difference in the effect of these two receptor-recognized alpha 2Ms is unknown. PDGF secreted by rat alveolar macrophages is bound to homologues of human alpha 2M and it has been suggested that PDGF action in the lung is tightly controlled during normal tissue remodeling. It is important to consider another regulator of PDGF termed SPARC (secreted protein, acidic and rich in cysteine), which inhibits the binding of PDGF-BB and -AB to cell-surface PDGF-beta receptors. SPARC could modulate PDGF activity during inflammation and tissue repair by limiting the availability of dimers containing the PDGF B chain. Future studies should address the relative importance of SPARC and alpha 2M in regulating PDGF-induced chemotaxis and proliferation. During inflammation or during the progression of fibroproliferative lung disease, the regulation of PDGF might be lost. For example, oxidative bursts from inflammatory cells (neutrophils and eosinophils) functionally inactivate alpha 2M. Thus, inhaled environmental insults (particles and oxidants) could perturb the normal growth regulatory signaling system between cells via the network that includes cytokines, alpha 2M, and proteinases.
Bonner
J C
JC
Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D051381:Rats; D011971:Receptors, Immunologic / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000378:metabolism* / Q000494:pharmacology
D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010982:Platelet-Derived Growth Factor; D011971:Receptors, Immunologic; D000511:alpha-Macroglobulins