Abstract:IL-10 is an anti-inflammatory cytokine. During infection it inhibits the activity of Th1 cells, NK cells, and macrophages, all of which are required for optimal pathogen clearance but also contribute to tissue damage. In consequence, IL-10 can both impede pathogen clearance and ameliorate immunopathology. Many different types of cells can produce IL-10, with the major source of IL-10 varying in different tissues or during acute or chronic stages of the same infection. The priming of these various IL-10-produci… Show more
“…IL-12 is considered a link between innate and adaptive immunity (48,49), and may be related to the pathogenesis of periodontal disease (50)(51)(52). Another interesting observation in the present study is that the production of the anti-inflammatory cytokine IL-10 was increased in response to LDD, possibly potentiating its beneficial effects to the host (53). This is an important finding as the relative IL-1beta/IL-10 ratio has been shown to be higher in aggressive periodontitis patients than periodontally healthy subjects (54).…”
Section: Actinomycetemcomitans Lps (42) In Other Experimental Systemsupporting
Doxycycline is an antibiotic used in the treatment of a variety of inflammatory conditions, including periodontitis. Apart from its antimicrobial properties, this drug also has independent antiinflammatory effects at sub-antimicrobial doses. The present study aimed to investigate the effects of low-doses of doxycycline (LDD) on cytokine production by human monocytic cells challenged with the periodontal pathogen Aggregatibacter actinomycetemcomitans, for up to 6h. The simultaneous regulation of 12 cytokines were measured by a Human Cytokine Array Kit. To validate the array findings, selected cytokines were also measured by enzyme-linked immunosorbant assay (ELISA). A. actinomycetemcomitans stimulated the production of tumor necrosis factor (TNF)-, interleukin (IL)-1 , IL-1 , IL-6 and IL-8 by the cells after 6h of challenge, and doxycycline significantly inhibited this effect. The kinetics of this regulation demonstrated an early (within 2h) and significant (P<0.05) inhibition of pro-inflammatory cytokines, with a mild (0.5-fold) up-regulation of the anti-inflammatory cytokine IL-10. The results indicate that LDD acts as an anti-inflammatory agent in human monocytic cells stimulated with A. actinomycetemcomitans. This model provides clear evidence that some of the clinically proven benefits of LDD may be related to its ability to regulate inflammatory mediator release by monocytic cells. This property may contribute to the clinically proven benefits of this antibiotic as an adjunctive treatment for periodontitis.
“…IL-12 is considered a link between innate and adaptive immunity (48,49), and may be related to the pathogenesis of periodontal disease (50)(51)(52). Another interesting observation in the present study is that the production of the anti-inflammatory cytokine IL-10 was increased in response to LDD, possibly potentiating its beneficial effects to the host (53). This is an important finding as the relative IL-1beta/IL-10 ratio has been shown to be higher in aggressive periodontitis patients than periodontally healthy subjects (54).…”
Section: Actinomycetemcomitans Lps (42) In Other Experimental Systemsupporting
Doxycycline is an antibiotic used in the treatment of a variety of inflammatory conditions, including periodontitis. Apart from its antimicrobial properties, this drug also has independent antiinflammatory effects at sub-antimicrobial doses. The present study aimed to investigate the effects of low-doses of doxycycline (LDD) on cytokine production by human monocytic cells challenged with the periodontal pathogen Aggregatibacter actinomycetemcomitans, for up to 6h. The simultaneous regulation of 12 cytokines were measured by a Human Cytokine Array Kit. To validate the array findings, selected cytokines were also measured by enzyme-linked immunosorbant assay (ELISA). A. actinomycetemcomitans stimulated the production of tumor necrosis factor (TNF)-, interleukin (IL)-1 , IL-1 , IL-6 and IL-8 by the cells after 6h of challenge, and doxycycline significantly inhibited this effect. The kinetics of this regulation demonstrated an early (within 2h) and significant (P<0.05) inhibition of pro-inflammatory cytokines, with a mild (0.5-fold) up-regulation of the anti-inflammatory cytokine IL-10. The results indicate that LDD acts as an anti-inflammatory agent in human monocytic cells stimulated with A. actinomycetemcomitans. This model provides clear evidence that some of the clinically proven benefits of LDD may be related to its ability to regulate inflammatory mediator release by monocytic cells. This property may contribute to the clinically proven benefits of this antibiotic as an adjunctive treatment for periodontitis.
“…The majority of IL‐10 is produced by macrophages and dendritic cells and with lessor amounts produced by T and B cells47 including B1a cells 5, 8. Consistent with these reports, we found that RMT1‐10 treatment increases IL‐10‐expressing B1a cells without affecting plasma IL‐10 levels.…”
BackgroundPeritoneal B1a cells attenuate atherosclerosis by secreting natural polyclonal immunoglobulin M (IgM). Regulatory B cells expressing T‐cell immunoglobulin mucin domain‐1 (TIM‐1) expanded through TIM‐1 ligation by anti‐TIM‐1 monoclonal antibody (RMT1‐10) induces immune tolerance.Methods and ResultsWe examined the capacity of RMT1‐10 to expand peritoneal B1a cells to prevent atherosclerosis development and retard progression of established atherosclerosis. RMT1‐10 treatment selectively doubled peritoneal B1a cells, tripled TIM‐1+ B1a cells and increased TIM‐1+IgM+interleukin (IL)‐10+ by 3‐fold and TIM‐1+IgM+IL‐10− B1a cells by 2.5‐fold. Similar expansion of B1a B cells was observed in spleens. These effects reduced atherosclerotic lesion size, increased plasma IgM and lesion IgM deposits, and decreased oxidatively modified low‐density lipoproteins in lesions. Lesion CD4+ and CD8+ T cells, macrophages and monocyte chemoattractant protein‐1, vascular cell adhesion molecule‐1, expression of proinflammatory cytokines monocyte chemoattractant protein‐1, vascular cell adhesion molecule‐1, IL1β, apoptotic cell numbers and necrotic cores were also reduced. RMT1‐10 treatment failed to expand peritoneal B1a cells and reduce atherosclerosis after splenectomy that reduces B1a cells, indicating that these effects are B1a cell‐dependent. Apolipoprotein E‐KO mice fed a high‐fat diet for 6 weeks before treatment with RMT1‐10 also increased TIM‐1+IgM+
IL‐10+ and TIM‐1+IgM+
IL‐10− B1a cells and IgM levels and attenuated progression of established atherosclerosis.Conclusions
RMT1‐10 treatment attenuates atherosclerosis development and progression by selectively expanding IgM producing atheroprotective B1a cells. Antibody‐based in vivo expansion of B1a cells could be an attractive approach for treating atherosclerosis.
“…In contrast to tumor-associated regulatory responses, B cells showed a dramatic decrease in IL-10 production compared to controls (Figure 4f). 20 As in allergic responses we also found an intense eosinophil infiltration in the tumor microenvironment of IL-33 treated mice (Figure 4g). 21 Taken together, these data suggest that direct peritoneal delivery of IL-33 can mediate an allergic-like CD4 T-cell activation and expansion, which mediates eosinophil recruitment and promotes uniquely B-cell activation with predominant class switching into IgE and decrease in production of IL-10.10.1080/2162402X.2018.1515058-F0004Figure 4.IL-33 promotes peritoneal CD4 T-cell and B cell activation and eosinophil recruitment. (A) Real-time quantitative-PCR of IL-5 expression in CD4 + T-cells sorted from the peritoneal cavity of mice bearing intraperitoneal ID8- Defb29/Vegf-a syngeneic tumors treated intraperitoneally with IL-33 or PBS (triplicates, pooled from 5 mice per group, 2 independent experiments).…”
Ovarian cancer is frequently diagnosed as peritoneal carcinomatosis. Unlike other tumor locations, the peritoneal cavity is commonly exposed to gut-breaching and ascending genital microorganisms and has a unique immune environment. IL-33 is a local cytokine that can activate innate and adaptive immunity. We studied the effectiveness of local IL-33 delivery in the treatment of cancer that has metastasized to the peritoneal cavity. Direct peritoneal administration of IL-33 delayed the progression of metastatic peritoneal cancer. Prolongation in survival was not associated with a direct effect of IL-33 on tumor cells, but with major changes in the immune microenvironment of the tumor. IL-33 promoted a significant increase in the leukocyte compartment of the tumor immunoenvironment and an allergic cytokine profile. We observed a substantial increase in the number of activated CD4+ T-cells accompanied by peritoneal eosinophil infiltration, B-cell activation and activation of peritoneal macrophages which displayed tumoricidal capacity. Depletion of CD4+ cells, eosinophils or macrophages reduced the anti-tumor effects of IL-33 but none of these alone were sufficient to completely abrogate its positive benefit. In conclusion, local administration of IL-33 generates an allergic tumor environment resulting in a novel approach for treatment of metastatic peritoneal malignancies, such as advanced ovarian cancer.
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