During inflammation, monocytes are recruited from the circulation to inflamed tissues where they are activated by multiple inflammatory mediators. As the initiating agents are eliminated and inflammation wanes, the monocytes are no longer necessary and must be removed from the tissues to resolve inflammation. Failure in this removal process may become pathogenic, and many chronic inflammatory conditions, including rheumatoid and experimentally-induced arthritis, are associated with the persistent accumulation of monocytes. Therefore, understanding the mechanisms which control normal monocyte deletion and potential aberrancies may underlie the development of strategies for modulating chronic inflammatory pathology. In this regard, apoptosis which represents a fundamental mechanism for eliminating unwanted cells in the midst of living tissues, may play a role in controlling monocyte accumulation at an inflammatory lesion. In fact, human monocytes have been shown to undergo apoptosis when exogenous growth or activating factors are withdrawn, and this process of death is reversed by LPS, IL-1B, and TNFalpha. Interestingly, this activation-dependent survival of monocytes is abolished by IL-4, a TH2 lymphocyte-derived anti-inflammatory cytokine and also by triggering of Fas (APO-1/CD95), a widely expressed apoptotic receptor. The positive and negative regulation of monocyte apoptosis by inflammatory cytokines supports the hypothesis that apoptosis is a critical pathway for the depletion of activated monocytes at inflammatory sites. To characterize intracellular pathways leading to monocyte death, we have explored the involvement of reactive oxygen intermediates (ROI), protein kinase C (PKC), and Bcl-2, which function to control apoptosis in other systems. Our results indicate that monocytes have at least two discrete pathways regulating their own life-span. Further unraveling of these dichotomous routes of monocyte apoptosis may not only provide new molecular clues in the apoptotic signaling cascade, but also identify potential targets for regulating this crucial inflammatory process.
