Evidence for a dual mechanism for IL-10 suppression of TNF-alpha production that does not involve inhibition of p38 mitogen-activated protein kinase or NF-kappa B in primary human macrophages
| Autor: | Irina A. Udalova, Jamie Campbell, Clive Smith, Agnes Denys, Lynn M. Williams, Dominic Kwaitkowski, Caroline Andrews, Cathleen J. Ciesielski, Brian M. J. Foxwell |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Lipopolysaccharides
RNA Stability p38 mitogen-activated protein kinases medicine.medical_treatment Immunology Biology p38 Mitogen-Activated Protein Kinases Adenoviridae Genes Reporter Gene expression medicine Humans Immunology and Allergy Luciferase RNA Messenger Enzyme Inhibitors Promoter Regions Genetic Protein kinase A 3' Untranslated Regions Cells Cultured Reporter gene Tumor Necrosis Factor-alpha Macrophages NF-kappa B Zymosan NFKB1 Molecular biology Interleukin-10 Enzyme Activation Cytokine Gene Expression Regulation Tumor necrosis factor alpha Mitogen-Activated Protein Kinases 5' Untranslated Regions Immunosuppressive Agents |
| Popis: | IL-10 is a potent anti-inflammatory cytokine and inhibitor of TNF-α production. The molecular pathways by which IL-10 inhibits TNF-α production are obscure, with diverse mechanisms having been published. In this study, a new approach has been taken for the study of human cells. Adenovirus was used to deliver TNF-α promoter-based luciferase reporter genes to primary human monocytic cells. The reporter genes were highly responsive to macrophage activation and appeared to mirror the behavior of the endogenous TNF-α gene. When added, either with or after the stimulus, IL-10 required the 3′ untranslated region of the TNF-α gene to inhibit luciferase mRNA and protein expression, indicating a posttranscriptional mechanism. However, if macrophages were incubated with IL-10 before activation, inhibition of gene expression was also mediated by the 5′ promoter, suggesting a transcriptional mechanism. To our knowledge, this is the first time that a dual mechanism for IL-10 function has been demonstrated. Studies to elucidate the mechanisms underlying the inhibition of TNF-α production addressed the effect of IL-10 on the activation of p38 mitogen-activated protein kinase and NF-κB. However, these studies could demonstrate no requirement for the inhibition of p38 mitogen-activated protein kinase or NF-κB activation as potential mechanisms. Overall, these results may explain the diversity previously ascribed to the complex mechanisms of IL-10 anti-inflammatory activity. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|