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Home / Arthritis News / Possible new role for NF-kB in the resolution of inflammation

Possible new role for NF-kB in the resolution of inflammation

April 13, 2005 By Arthritis Center

Nuclear factor-kB (NF-kB) is a transcription factor thought to play an important role in onset of inflammation. Thus it is intuitive that NF-kB has become a candidate target for new anti-inflammatory treatments; however, the mechanisms that govern the resolution of inflammation are poorly understood. In this study Lawrence et al (Nature Medicine 7:1291, 2001), investigated the roles of NF-kB in the onset and resolution of inflammation.

NF-kB activation in leukocytes during the evolution of inflammation was measured using rat carrageenin-induced pleurisy as a model of acute inflammation. In this model, inflammation peaks at 24 hours and resolves by 48 hours. NF-kB activity was detected at 6 hours and increased at 24 and 48 hours. At the onset of inflammation, NF-kB activation was coincident with the expression of the pro-inflammatory marker iNOS, while during resolution NF-kB activation occurred with an increased expression of COX-2 and no expression of iNOS. COX-2 expression was biphasic, peaking at 6 hours and again at 48 hours.

To determine the effects of NF-kB inhibition during inflammation, the NF-kB inhibitor pyrrolidine dithiocarbamate (PDTC) was given at both the 6 hour onset peak and at 24-hours. When treated with PDTC during the onset of the inflammation, pleuritic exudate formation was reduced by 45% (P<0.001). The number of leukocytes was reduced by 26% (P<0.001). However, when given at 24 hours, PDTC lengthened the inflammatory response and led to a seven-fold increase in exudate volume and a 2.3-fold increase in leukocytes (P<0.001) at 48 hours.

The preceding findings were confirmed using other NF-kB inhibitors, as well as in a mouse model of inflammation-the mouse carrageenin air pouch.

Lawrence et al, next examined the relationship between NF-kB inhibition and leukocyte programmed cell death and transforming growth factor-Β1 (TGF-Β1) release. TGF-Β1 release is thought to occur as an apoptotic cell is being phagocytosed by a macrophage. It was found that administration of PDTC reduced TGF-Β1 release by 50% and decreased the number of leukocytes undergoing programmed cell death by approximately 40%.

Summary:

NF-kB is associated with the expression of pro-inflammatory genes during the onset of inflammation and with the expression of anti-inflammatory genes during the resolution of inflammation. Inhibition of NF-kB at the onset of inflammation results in decreased inflammatory response, but inhibition of NF-kB during inflammation protracts the inflammatory response. Additionally, NF-kB inhibition during the inflammatory process is associated with the production and release of TGF-Β1 and a decrease in the number of apoptotic leukocytes. The data suggest that NF-kB plays a role in the resolution of inflammation through the regulation of leukocyte apoptosis.

Editorial Comment:

The mechanism of resolution of acute inflammation such as in gout is poorly understood. Understanding endogenous anti-inflammatory mechanisms may also enable us to better comprehend persistent inflammation in disease states such as rheumatoid arthritis. This study offers new insight into the divergent roles of one transcription factor in this process. As the authors point out, the use of an NF-kB inhibitor in vivo may not be a viable therapeutic approach since acute and chronic stages of inflammation cannot be clearly separated.

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