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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.
J Immunol. 2002 May 15; 168(10):4837-45.JI

Abstract

IL-10 is a potent anti-inflammatory cytokine and inhibitor of TNF-alpha production. The molecular pathways by which IL-10 inhibits TNF-alpha 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-alpha 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-alpha gene. When added, either with or after the stimulus, IL-10 required the 3' untranslated region of the TNF-alpha 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-alpha production addressed the effect of IL-10 on the activation of p38 mitogen-activated protein kinase and NF-kappaB. However, these studies could demonstrate no requirement for the inhibition of p38 mitogen-activated protein kinase or NF-kappaB activation as potential mechanisms. Overall, these results may explain the diversity previously ascribed to the complex mechanisms of IL-10 anti-inflammatory activity.

Authors+Show Affiliations

Kennedy Institute of Rheumatology Division, Imperial College Faculty of Medicine, Charing Cross Campus, 1 Aspenlea Road, London, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11994432

Citation

Denys, Agnes, et al. "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." Journal of Immunology (Baltimore, Md. : 1950), vol. 168, no. 10, 2002, pp. 4837-45.
Denys A, Udalova IA, Smith C, et al. 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. J Immunol. 2002;168(10):4837-45.
Denys, A., Udalova, I. A., Smith, C., Williams, L. M., Ciesielski, C. J., Campbell, J., Andrews, C., Kwaitkowski, D., & Foxwell, B. M. (2002). 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. Journal of Immunology (Baltimore, Md. : 1950), 168(10), 4837-45.
Denys A, et al. 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. J Immunol. 2002 May 15;168(10):4837-45. PubMed PMID: 11994432.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Denys,Agnes, AU - Udalova,Irina A, AU - Smith,Clive, AU - Williams,Lynn M, AU - Ciesielski,Cathleen J, AU - Campbell,Jamie, AU - Andrews,Caroline, AU - Kwaitkowski,Dominic, AU - Foxwell,Brian M J, PY - 2002/5/8/pubmed PY - 2002/6/20/medline PY - 2002/5/8/entrez SP - 4837 EP - 45 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 168 IS - 10 N2 - IL-10 is a potent anti-inflammatory cytokine and inhibitor of TNF-alpha production. The molecular pathways by which IL-10 inhibits TNF-alpha 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-alpha 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-alpha gene. When added, either with or after the stimulus, IL-10 required the 3' untranslated region of the TNF-alpha 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-alpha production addressed the effect of IL-10 on the activation of p38 mitogen-activated protein kinase and NF-kappaB. However, these studies could demonstrate no requirement for the inhibition of p38 mitogen-activated protein kinase or NF-kappaB activation as potential mechanisms. Overall, these results may explain the diversity previously ascribed to the complex mechanisms of IL-10 anti-inflammatory activity. SN - 0022-1767 UR - https://www.unboundmedicine.com/medline/citation/11994432/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_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=11994432 DB - PRIME DP - Unbound Medicine ER -