Macrophages are phagocytic cells that accumulate in inflammatory sites. In addition to phagocytosis and subsequent antigen processing and presentation, macrophages also express cell surface molecules and secrete a wide variety of different cytokines, including IL-1,IL-6, IL-8, IL-12, and TNF-a, upon exposure to pathogens and cancer cells. Therefore, macrophages could have local and systemic effects and serve not only to amplify the innate immune response, but also to trigger adaptive immunity.
Although resting human monocytes do not express CD137 mRNA, their expression could be upregulated rapidly by IL-1 or PMA (Schwarz et al., 1995). Another study has shown that cell surface CD137 could be detected by only a brief culture of monocytes in media (Kienzle and von Kempis, 2000). Of importance is the stimulation of monocytes by anti-CD137 mAb which upregulated mRNA expression of TNF-a and IL-8, whereas it also downregulated IL-10 expression (Kienzle and von Kempis, 2000). In a CD137+ monocytic line THP-1, cross-linking by anti-CD137 mAb upregulated CD54 and CD11b and increased adhesion of THP-1 cells to extracellular matrix proteins, in addition to increased secretion of IL-8 and TNF-a. Increased adhesion could be suppressed by an inhibitor of mitogen-activated protein kinase kinase (MEK), but not by a p38 kinase inhibitor (Choi et al., 2005). These results suggest that CD137 on monocytes is functional. Interestingly, CD137-stimulated monocytes were found to promote B cell apoptosis in a cell-contact dependent fashion (Kienzle and von Kempis, 2000). Therefore, CD137 signal may inhibit humoral immune response through monocyte activation. This observation is consistent with the finding that B cells were progressively deleted in CD137L transgenic mice, in which the expression of CD137L is under the control ofMHC class II I-Ea promoter (Zhu et al., 2001). It has also been shown that administration of agonistic mAb to CD137 could inhibit T cell-dependent antibody response to sRBC (Mittler et al., 1999) and autoantibodies in several systemic autoimmunity models (Foell et al., 2003; Mittler et al., 2004).
In addition to CD137, monocytes and macrophages also express high levels of CD137L and its expression is tightly controlled by cytokines. In several in vitro studies using human monocyte culture systems, CD137 protein is shown to be a potent monocyte activation factor. The plate-bound CD137 protein induced the expression of IL-6, IL-8, and TNF-a, and inhibits expression of IL-10, therefore supporting that the effect of CD137 is mediated through CD137L as a counter-receptor for monocytes/macrophages (Ju et al., 2003). CD137 engagement also induced expression of ICAM-1 and reduced expression of Fcy receptor III. The effect does not seem to be non-specific since levels of HLA-DR remain constant. Importantly, the engagement of CD137L on macrophages promotes vigorous proliferation and survival. This effect is found in part due to, the elevated macrophage colony-stimulating factor (Langstein and Schwarz, 1999), an essential monocyte survival factor.
Monocytes/macrophages express both CD137 and CD137L and are both capable of transducing activation signals. Therefore, this may represent a unique amplification system for boosting macrophage functions during inflammation and pathogen infection. However, there is not yet direct evidence to validate this mode in the activation of monocytes. Experiments thus far are all performed in a cell culture system, and how this mode contributes to the overall process of immune responses or inflammation is not yet clear, especially in vivo. Another area to be explored is the interactions through CD137-CD137L among macrophages with other cells which are key players of innate immunity. These cells include NK cells, DCs, and granulocytes, which are capable of expressing CD137 and/or CD137L. These issues could be solved by reconstitution experiments employing CD137 or CD137L deficient cellular components in the near future.
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