ROLE OF CYTOKINES AND INFLAMMATORY MEDIATORS IN TISSUE DESTRUCTION

Colonization or emergence of microbial pathogens may result in tissue destruction by activation of one or more of five distinct host degrada tive pathways (matrix metalloproteinase pathway, plasminogen-dependent pathway, phagocytic pathway, PMN-serine proteinase pathway and osteoc lastic bone resorption) or by direct cleavage of extracellular matrix constituents by microbial proteinases. Activation of endogenous destru ctive pathways may be mediated by immune responses resulting in expres sion of degradative cellular phenotypes among both immigrant and resid ent cell populations. In addition, expression of degradative phenotype s may be triggered by direct influences on host cells of microbial pro ducts (LPS, enzymes, toxins). A body of evidence suggests that each of these mechanisms involves local production of proinflammatory cytokin es and growth factors. The matrix metalloproteinase pathway is central ly involved in dissolution of all unmineralized connective tissues and perhaps in resorption of bone as well. The matrix metalloproteinase f amily consists of nine or more genetically distinct Zn++ endopeptidase s which collectively cleave all of the constituents of the extracellul ar matrix. Recent studies have uncovered many essential elements of a complex, but still incomplete, regulatory network that governs tissue destruction. Proinflammatory cytokines and growth factors induce signa lling pathways several of which are dependent on protein kinase C and result in transient expression of the transcription factors c-jun and c-fos. Initiation of transcription of most matrix metalloproteinase ge nes requires binding of the transcription factor AP-1 (c-jun/c-fos) to a specific promoter sequence but attainment of maximal transcription rates is dependent on interaction with other promoter elements as well . Several matrix metalloproteinases have been detected in crevicular f luids and tissues of inflamed human gingiva as have the proinflammator y cytokines (IL-1 and TNF-alpha) which regulate their transcription. A lthough the mere presence of enzymes and cytokines does not necessaril y impart function per se, these observations suggest that some level o f spatial or temporal linkage exists between metalloproteinase/cytokin e expression and gingival inflammation.