Reduced infiltration and increased apoptosis of leukocytes at sites of inflammation by systemic administration of a membrane-permeable IκBα repressor
✍ Scribed by Nathan M. Blackwell; Phupinder Sembi; Justine S. Newson; Toby Lawrence; Derek W. Gilroy; Panagiotis S. Kabouridis
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- English
- Weight
- 272 KB
- Volume
- 50
- Category
- Article
- ISSN
- 0004-3591
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✦ Synopsis
Abstract
Objective
NF‐κB activation is associated with several inflammatory disorders, including rheumatoid arthritis (RA), making this family of transcription factors a good target for the development of antiinflammatory treatments. Although inhibitors of the NF‐κB pathway are currently available, their specificity has not been adequately determined. IκBα is a physiologic inhibitor of NF‐κB and a potent repressor experimentally when expressed in a nondegradable form. We describe here a novel means for specifically regulating NF‐κB activity in vivo by administering a chimeric molecule comprising the super‐repressor IκBα (srIκBα) fused to the membrane‐transducing domain of the human immunodeficiency virus Tat protein (Tat‐srIκBα).
Methods
The Wistar rat carrageenan‐induced pleurisy model was used to assess the effects of in vivo administration of Tat‐srIκBα on leukocyte infiltration and on cytokine and chemokine production.
Results
Systemic administration of Tat‐srIκBα diminished infiltration of leukocytes into the site of inflammation. Analysis of the recruited inflammatory cells confirmed uptake of the inhibitor and reduction of the NF‐κB activity. These cells exhibited elevated caspase activity, suggesting that NF‐κB is required for the survival of leukocytes at sites of inflammation. Analysis of exudates, while showing decreases in the production of the proinflammatory cytokines tumor necrosis factor α and interleukin‐1β, also revealed a significant increase in the production of the neutrophil chemoattractants cytokine‐induced neutrophil chemoattractant 1 (CINC‐1) and CINC‐3 compared with controls. This result could reveal a previously unknown feedback mechanism in which infiltrating leukocytes may down‐regulate local production of these chemokines.
Conclusion
These results provide new insights into the etiology of inflammation and establish a strategy for developing novel therapeutics by regulating the signaling activity of pathways known to function in RA.