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IL-10 inhibits cytokine production by activated macrophages
D F Fiorentino1, A Zlotnik, T R Mosmann
1DNAX Research Institute, Palo Alto, CA 94304.
Insights
Interleukin-10 (IL-10) significantly inhibits macrophage production of inflammatory cytokines like IL-1, IL-6, and TNF-alpha. This cytokine also impacts macrophage morphology, suggesting a key role in regulating immune responses.
Area of Science:
- Immunology
- Cell Biology
Background:
- Interleukin-10 (IL-10) is known to regulate immune cell function.
- Macrophages are critical antigen-presenting cells (APCs) involved in immune responses.
Purpose of the Study:
- To investigate the direct effects of IL-10 on macrophage cell lines and primary macrophages.
- To determine IL-10's impact on cytokine production and gene expression in macrophages.
Main Methods:
- Macrophage cell lines and primary peritoneal macrophages were treated with IL-10.
- Lipopolysaccharide (LPS) and Interferon-gamma (IFN-gamma) were used to stimulate cytokine production.
- Cytokine protein levels were measured using ELISA, and mRNA expression was analyzed by polymerase chain reaction and Northern blot.
Main Results:
- IL-10 significantly inhibited LPS-induced production of IL-1, IL-6, and TNF-alpha proteins and mRNA in macrophage cell lines.
- IL-10 was a more potent inhibitor of monokine synthesis than IL-4.
- Endogenous IL-10 in peritoneal macrophages contributed to reduced monokine synthesis.
- IFN-gamma enhanced IL-6 production by suppressing endogenous IL-10 production.
Conclusions:
- IL-10 potently inhibits macrophage monokine synthesis, affecting both protein and mRNA levels.
- IL-10 plays a significant role in regulating acute inflammatory responses and T cell activation.
- Endogenous IL-10 production by macrophages influences their response to inflammatory stimuli.
Abstract:
IL-10 inhibits the ability of macrophage but not B cell APC to stimulate cytokine synthesis by Th1 T cell clones. In this study we have examined the direct effects of IL-10 on both macrophage cell lines and normal peritoneal macrophages. LPS (or LPS and IFN-gamma)-induced production of IL-1, IL-6, and TNF-alpha proteins was significantly inhibited by IL-10 in two macrophage cell lines. Furthermore, IL-10 appears to be a more potent inhibitor of monokine synthesis than IL-4 when added at similar concentrations. LPS or LPS- and IFN-gamma-induced expression of IL-1 alpha, IL-6, or TNF-alpha mRNA was also inhibited by IL-10 as shown by semiquantitative polymerase chain reaction or Northern blot analysis. Inhibition of LPS-induced IL-6 secretion by IL-10 was less marked in FACS-purified peritoneal macrophages than in the macrophage cell lines. However, IL-6 production by peritoneal macrophages was enhanced by addition of anti-IL-10 antibodies, implying the presence in these cultures of endogenous IL-10, which results in an intrinsic reduction of monokine synthesis after LPS activation. Consistent with this proposal, LPS-stimulated peritoneal macrophages were shown to directly produce IL-10 detectable by ELISA. Furthermore, IFN-gamma was found to enhance IL-6 production by LPS-stimulated peritoneal macrophages, and this could be explained by its suppression of IL-10 production by this same population of cells. In addition to its effects on monokine synthesis, IL-10 also induces a significant change in morphology in IFN-gamma-stimulated peritoneal macrophages. The potent action of IL-10 on the macrophage, particularly at the level of monokine production, supports an important role for this cytokine not only in the regulation of T cell responses but also in acute inflammatory responses.