Inhibition of signal transduction pathways involved in inflammation.

In order to target inflammatory processes effectively, it is necessary to understand, within an eukaryotic cell, how inflammatory reactions are generated and maintained. Therefore, this article will first concentrate on the signal transduction pathways and molecular mechanisms that drive inflammatory gene expression, followed by countering some of the published hypotheses that try to explain the inhibitory role of glucocorticoids. The current working model is included, which explains glucocorticoid action, and additionally points to an alternative or cooperative way of how to block inflammatory gene expression. Although inflammatory processes produce different diseases, depending on the inflamed tissue or organ involved, all of these afflictions have common aspects or common cellular processes, such as the activation of a stress signalling pathway and the concomitant production of inflammatory cytokines. In order to understand the inflammatory process at the “molecular” level and thus devise more specific molecular targets for the development of novel anti­inflammatory drugs, the author's group has studied signal transduction pathways and gene regulatory mechanisms that drive the expression of inflammatory genes. In particular, they studied the induction of interleukin (IL)‐6 and other related gene promoters in mouse fibroblasts, in response to inflammatory stimuli such as tumour necrosis factor (TNF), and found that the transcription factor nuclear factor (NF)‐κB is crucial for transcriptional induction of these genes. This factor is a heterodimeric complex, composed of two subunits, a p50 deoxyribonucleic acid (DNA)‐binding subunit and a p65 DNA‐binding and transcriptionally active subunit. In the resting state of the cell, the NF‐κB complex is stored and kept inactive in the cell by an inhibitory molecule, IκB. As a result of various inflammatory stimuli, this inhibitor becomes subject to complete targeted degradation, releasing the NF‐κB complex, allowing it to migrate to the nucleus and to bind onto NF‐κB‐ responsive sequences present in various cellular promoters. …