In response to a trigger, such as an injury or an antigen, cells in affected tissue produce signals to initiate the infiltration of white blood cells (such as monocytes, granulocytes, and lymphocytes) to the site.
Once these cells move from the blood vessels into the tissue, they attack microorganisms and bacteria and ingest senescent cells and cellular debris in a process called phagocytosis. Along with the resident tissue cells, these cells produce inflammatory mediators that result in vasodilation, edema, and cell proliferation.
This inflammatory response occurs through a sequence of metabolic events that involves five types of agents: (1) cytokines, such as the interleukins, which induce cellular production of chemokines and growth factors; (2) chemokines, which attract or re- cruit cells to the site; (3) arachidonic acid metabolites, such as prostaglandins and leukotrienes, which induce enzyme production and activation; (4) growth factors, which stimulate cell proliferation; and (5) catabolic enzymes, such as matrix metalloproteinase (MMP), which degrade the extracellular ma- trix (ECM). The cascade is perpetuated by the cellular response to the autocrine, para- crine, and endocrine effects of these same agents (Fig. 1).
When a cytokine binds to its specific receptor on the cell membrane, the receptor mediates activation of protein kinase-C, which by intracellular phosphorylation pro- duces transcription factors, such as activation protein-1 (AP-1) and nuclear factor κB (NFκB). Upon phosphorylation, the NFκB complex is cleaved and passes into the nucleus where it binds to the promoter region of genes responsible for expression of inflammatory proteins1 (Fig. 2).
An AP-1 binding site is located on the promoter for MMP genes. In conjunction with other sites on the promoter, binding of AP-1 to the AP-1 bind- ing site leads to transcriptional activation of the MMP genes and subsequent production of MMP as proenzymes.2-4
Activation of AP-1 and NFκB stimulates the synthesis of chemokines and adhesion mol- ecules that promote recruitment and infiltra- tion of mononuclear cells. This activation also produces cytokines and growth factors that per- petuate the immune response and proenzymes such as MMPs that degrade matrix proteins. In addition, enzymes that initiate the arachi- donic acid cascade and production of eicosanoids are produced. For example, tumor necrosis factor-α (TNF-α) and interleukin (IL)-6, both of which are cytokines associat- ed with inflammation, have been shown to stimulate the messenger RNA responsible for production of inflammatory cytokines through activation of NFκB and AP-1. Thus, the pres- ence of a cytokine can promote synthesis of itself and other cytokines.
Another cytokine, IL-1, also has been shown to activate MMP. When activated, MMP enzymes degrade the ECM in the vi- cinity of the cell. Degradative products of the ECM derived from MMP activity can stimu- late chemokines, which then recruit phago- cytic cells to the site. Infiltration of leuko- cytes produces additional cytokines, and the process continues until the inducing agent is eliminated.