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IL-10 receptor dysfunction in macrophages during chronic inflammation.
R Avdiushko1, D Hongo, H Lake-Bullock
1Department of Microbiology and Immunology, University of Kentucky, College of Medicine, Lexington 40536-0084, USA.
Journal of Leukocyte Biology
|October 9, 2001
Summary
Mice infected with LP-BM5 retrovirus showed reduced macrophage response to interleukin-10 (IL-10), impacting inflammation control. This hyporesponsiveness, linked to tumor necrosis factor-alpha, suggests a mechanism for chronic inflammatory diseases.
Area of Science:
- Immunology
- Molecular Biology
- Pathology
Background:
- Interleukin-10 (IL-10) is an immunosuppressive cytokine with therapeutic potential for inflammatory diseases.
- Therapeutic efficacy of IL-10 depends on immune cell responsiveness.
- Chronic infections can alter immune cell function and cytokine signaling.
Purpose of the Study:
- To investigate the effect of chronic LP-BM5 retroviral infection on macrophage responsiveness to IL-10.
- To identify mechanisms underlying altered IL-10 signaling in macrophages during chronic infection.
- To explore the implications of IL-10 hyporesponsiveness in chronic inflammatory conditions.
Main Methods:
- Macrophage isolation from retrovirus-infected and uninfected mice (alveolar, peritoneal, bone marrow-derived).
- In vitro assessment of IL-10's ability to inhibit lipopolysaccharide-induced TNF-alpha and IL-6 production.
- Exposure of macrophages to TNF-alpha and interferon-gamma to study their role in IL-10 hyporesponsiveness.
- Reverse transcriptase-PCR and flow cytometry to analyze IL-10 receptor expression.
Main Results:
- Macrophages from chronically infected mice exhibited significantly reduced responsiveness to IL-10.
- IL-10's inhibitory effect on TNF-alpha and IL-6 production was diminished in infected macrophages.
- Tumor necrosis factor-alpha (TNF-alpha), but not interferon-gamma, exposure reduced normal macrophage responsiveness to IL-10.
- IL-10 receptor alpha and beta chain expression remained normal in infected macrophages, ruling out receptor downregulation.
Conclusions:
- Chronic LP-BM5 retroviral infection induces IL-10 hyporesponsiveness in macrophages.
- TNF-alpha contributes to the development of IL-10 hyporesponsiveness.
- Altered IL-10 responsiveness may play a role in the chronicity of inflammation observed in this model and potentially other diseases.