Monocytes are a population of leukocytes that terminally differentiate into macrophages and DCs. Whereas these differentiated progeny have inflammatory and resident--which are more immunomodulatory--phenotypes, less has been reported on the plasticity of monocytes themselves. We found that MSCs, a population of somatic stem cells, can rapidly induce human and murine monocytes through secretion of HGF to acquire an immunomodulatory phenotype to suppress T cell effector function. MSCs are multilineage postnatal progenitor cells with strong immunomodulatory effects toward T lymphocytes, NK lymphocytes, and DCs, but less is known regarding their interactions with monocytes. We found that CD14(+) human monocytes express c-Met, the receptor for HGF, and both depletion of HGF-treated CD14(+) monocytes and knockdown of HGF secretion in MSCs abrogate the suppression of anti-CD3/28-activated T cell proliferation. HGF-treated monocytes remain undifferentiated and can alter activated T cell cytokine expression from a Th1 toward Th2 profile. Moreover, monocytes cocultured with MSCs or treated with HGF alone can produce high levels of IL-10, a potent immunomodulatory cytokine. Injection of HGF to WT mice also results in an increase in IL-10(+)-expressing monocytes from the spleen, a known reservoir for circulating monocytes. Mechanistically, HGFs modulate IL-10 production in monocytes through the ERK1/2 pathway. Our data demonstrate further the pleomorphic nature of MSC immunomodulation, as well as highlight the important role of immunomodulatory monocytes in altering T cell effector function.
Production of proinflammatory cytokines is implicated in the pathogenesis of viridans streptococcusinduced ␣-streptococcal shock syndrome and infective endocarditis. Streptococcus mutans, one of the opportunistic pathogens causing infective endocarditis, was reported previously to stimulate monocytes and epithelial and endothelial cells in vitro to produce various cytokines. We found that glucosyltransferases (GTFs) GtfC and GtfD of S. mutans stimulated predominantly the production of interleukin-6 (IL-6) from T cells cultured in vitro. The level of IL-6 but not of tumor necrosis factor alpha in blood was significantly elevated when rats were injected intravenously with S. mutans GS-5, whereas IL-6 was detected at a much lower level when rats were challenged with NHS1DD, an isogenic mutant defective in the expression of GTFs. The serum IL-6 level was elevated in patients with endocarditis caused by different species of viridans streptococci which express GTF homologues. Affinity column-purified GTFs reduced the levels of detectable IL-2 of T cells stimulated by another bacterial antigen, tetanus toxoid. These results suggested that GTFs might modulate the production of Th1-type cytokines and that GTFs of S. mutans play a significant role in stimulating the production of the proinflammatory cytokine IL-6 in vivo. Species of viridans streptococci, such as Streptococcus mutans, Streptococcus sanguis, orStreptococcus oralis, are common causes of infective endocarditis in humans (2, 13). In Taiwan, S. oralis and S. sanguis are most frequently isolated from blood cultures in endocarditis, but S. mutans, a primary etiological agent of human dental caries (14), is associated with the highest incidence of endocarditis in bacteremia-associated pyogenic infections (5). S. mutans and other oral streptococci may enter the bloodstream and cause transient bacteremia in humans following dental extractions, brushing of teeth, and chewing (9). Transient bacteremia facilitated S. mutans colonization of the valve tissues, particularly in those patients with preexisting valvular damage. The development of endocarditis depends on a balance between the abilities of the organism to adhere to vegetations and to resist the array of host responses.S. mutans was able to stimulate in vitro the proliferation of peripheral blood mononuclear cells (PBMC), including CD4 ϩ T cells, CD8 ϩ T cells, and natural killer (NK) cells, in an antigen-dependent manner (16). The stimulated PBMC secreted gamma interferon (IFN-␥), tumor necrosis factor  (TNF-), and interleukin 10 (IL-10), etc., but the level of detectable IL-2 was relatively low compared to that of the others when PBMC were stimulated by soluble factors secreted from S. mutans (16). Antigen I/II of S. mutans, an adhesin for saliva-coated surfaces, interacted directly with human monocytes or epithelial or endothelial cells through lectin-like binding and stimulated the production of proinflammatory cytokines, such as IL-1, IL-6, 20,22). The induction of excess proinflammatory cytokines, espe...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.