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Production That Does Not Involve Inhibition of p38 Mitogen-Activated Protein Kinase or NF-
B in Primary Human Macrophages1
* Kennedy Institute of Rheumatology Division, Imperial College Faculty of Medicine, Charing Cross Campus, London, United Kingdom; and
University Department of Paediatrics, John Radcliffe Hospital, Oxford, United Kingdom
IL-10 is a potent anti-inflammatory cytokine and
inhibitor of TNF-
production. The molecular pathways by which IL-10
inhibits TNF- 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-
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- gene. When added, either with or after
the stimulus, IL-10 required the 3' untranslated region of the
TNF- 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-
production addressed the effect of IL-10 on the activation of p38
mitogen-activated protein kinase and NF-
B. However, these studies
could demonstrate no requirement for the inhibition of p38
mitogen-activated protein kinase or NF-B activation as potential
mechanisms. Overall, these results may explain the diversity previously
ascribed to the complex mechanisms of IL-10 anti-inflammatory
activity.
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