Neutral proteinases secreted by macrophages degrade basic protein: a possible mechanism of inflammatory demyelination.
In the inflammatory demyelinating diseases, such as multiple sclerosis, Landry-Guillain-Barré syndrome and experimental allergic encephalomyelitis, demyelination occurs in the vicinity of infiltrating mononuclear cells. Although the histopathology is characteristic of each disease, the general observation that myelin destruction in inflammatory lesions begins prior to phagocytosis suggests a common mechanism for myelinolysis in these diseases. Recent studies show that stimulated macrophages secrete several neutral proteinases, including plasminogen (Plg) activator. We have tested the possibility that these proteinases could, directly or indirectly, initiate myelin destruction. Isolated brain myelin was incubated with supernatant media from cultures of stimulated mouse peritoneal macrophages in the presence and absence of Plg. Cell supernatants alone caused some degradation of basic protein (BP) in myelin. The amount degraded was considerably enhanced in the presence of Plg. The other myelin proteins remained essentially intact. While the Plg-independent proteolytic activity in the supernatants was abolished by EDTA, known to inhibit the neutral proteinases, the Plg-dependent hydrolysis was inhibited by p-nitrophenylguanidinobenzoate, an inhibitor of Plg activator and plasmin. These results suggested that the Plg activator secreted by the macrophages generated plasmin, which selectively degraded BP. This interpretation was confirmed by the observation that urokinase, a Plg activator, plus Plg was effective in degrading BP in myelin. We propose that the action of neutral proteinases released by stimulated macrophages, and its amplification by the Plg-plasmin system, may play a significant role in several inflammatory demyelinating diseases; and that the relative specificity of these reactions for myelin lies in the extreme susceptibility of BP to proteolysis.
D000818:Animals; D001921:Brain / Q000378:metabolism; D002415:Cats; D002417:Cattle; D003711:Demyelinating Diseases / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology*; D008970:Molecular Weight; D004676:Myelin Basic Protein / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D010958:Plasminogen / Q000378:metabolism; D010960:Plasminogen Activators / Q000378:metabolism
D004676:Myelin Basic Protein; D010958:Plasminogen; D010447:Peptide Hydrolases; D010960:Plasminogen Activators; D005341:Fibrinolysin