NF-κΒ inhibition is ineffective in blocking cytokine-induced IL-8 production but P38 and STAT1 inhibitors are effective.

Abstract

OBJECTIVE:

In vitro but not in vivo evidence indicates that blockade of NF-κB is effective in reducing inflammation and production of IL-8. We hypothesized that the failure of in vitro experiments to predict in vivo outcome was due to the use of short time periods of observation and the use of single cytokines to stimulate NF-κB.

METHODS:

HEK cells with a NF-κB reporter gene or CaCo-2 cells were stimulated with CM (IL-1-β; TNF-α, and IFN-γ) or individual cytokines in the presence and absence of NF-κB inhibitors, a STAT1 inhibitor, and/or a p38 MAPK inhibitor for periods up to 24 h. NF-κB activation, IL-8 production, and nitric oxide production were measured.

RESULTS:

CM-induced IL-8 production in HEK cells was additive to synergistic. CM enhanced production of IL-8 at 24 h but not 4 h was independent of NF-κB. The p38 inhibitor SB203580 and the STAT1 inhibitor EGCG blocked CM-induced IL-8 production at both early and late time periods. The NF-κB inhibitors PDTC and BAY11-7082 were found to increase CM-stimulated IL-8 production in Caco-2 cells at 24 h.

CONCLUSIONS:

Our data suggest an effective strategy to reduce IL-8 production is to block p38 or STAT1 rather than NF-κB.

• Authors: Quan Wang, Nathan Huber, Greg Noel, Lauren Haar, Yizhi Shan, Timothy A Pritts, Cora K Ogle
• Journal: Inflammation research : official journal of the European Histamine Research Society ... [et al.] (Inflamm Res) Vol. 61 Issue 9 Pg. 977-85 (Sep 2012) ISSN: 1420-908X [Electronic] Switzerland
• PMID: 22618201 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(4-methylphenylsulfonyl)-2-propenenitrile
• Cytokines
• Imidazoles
• NF-kappa B
• Nitriles
• Protein Kinase Inhibitors
• Pyridines
• STAT1 Transcription Factor
• STAT1 protein, human
• Sulfones
• Thiocarbamates
• prolinedithiocarbamate
• Nitric Oxide
• Catechin
• Proline
• epigallocatechin gallate
• p38 Mitogen-Activated Protein Kinases
• SB 203580

Topics

• Caco-2 Cells
• Catechin (analogs & derivatives, pharmacology)
• Cell Line
• Cytokines (antagonists & inhibitors, pharmacology)
• Genes, Reporter
• Humans
• Imidazoles (pharmacology)
• NF-kappa B (antagonists & inhibitors, genetics)
• Nitric Oxide (metabolism)
• Nitriles (pharmacology)
• Proline (analogs & derivatives, pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Pyridines (pharmacology)
• STAT1 Transcription Factor (antagonists & inhibitors)
• Sulfones (pharmacology)
• Thiocarbamates (pharmacology)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors)