Signal transduction in inflammatory processes, current and future therapeutic targets: A mini review

Summary

The selective control of inflammatory reactions will continue to be a major issue in the development of new drugs. Many new molecular targets are coming up. This paper highlights a few key mediators that are nowadays considered as interesting therapeutic intervention points. Cytokines play an important regulatory role in the initiation, maintenance and termination of inflammatory reactions. More than 50 cytokines have been identified, and more and more has become known about their receptors and signal transduction pathways. Tumour necrosis factor‐α (TNF‐α) is still regarded as one of the initial cytokines of the cascade, and different approaches are followed to control its synthesis, release or effects. Lipopolysaccharide (LPS) is a one of the triggers that is able to induce a strong TNF‐response. Inhibitors of cyclic nucleotide phosphodiesterases (PDEs), including rolipram and pentoxifylline suppress the LPS‐induced TNF‐α production in monocytes/ macrophages. In our laboratory it has been shown that the alternative way to increase cAMP levels, via stimulation of ß‐adrenergic receptors, also provides an effective way, both in vitro and in vivo, to inhibit TNF‐α release. Other therapeutic ways include the use of antibodies directed to cytokines, TNF receptor fused to IgG, antibody therapy against TNF, the use of MAP kinase inhibitors. The different signal transduction pathways, including the NF‐κB activation route may provide alternative pharmacological tools.

We may surely expect anti‐inflammatory drugs of much greater specificity to be developed in the next decade. Despite the relative limited investments in veterinary drug development this will also have consequences for veterinary therapy

Key words:

• Anti‐inflammatory therapy
• cytokines
• signal transduction
• NF‐κB
• lipopolysaccharide

Notes

Department of Veterinary Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80152, 3508 TD Utrecht, the Netherlands.

Department of Pharmacology, TNO Pharma, Zeist, the Netherlands.

Present adress : Department of Metabolism and Pharmacokinetics, Pharmacia & Upjohn, Viale Pasteur 10, 200014 Nerviano (MI), Italy.

Additional information

Notes on contributors

R. Witkamp

1 2

M. Monshouwer

1 3