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).
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.
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.
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.