Signal transduction networks in rheumatoid arthritis

Abstract

Signal transduction pathways regulate cellular responses to stress and play a critical role in inflammation. The complexity and specificity of signalling mechanisms represent major hurdles for developing effective, safe therapeutic interventions that target specific molecules. One approach is to dissect the pathways methodically to determine their hierarchy in various cell types and diseases. This approach contributed to the identification and prioritisation of specific kinases that regulate NF-kappa B and the mitogen activated protein (MAP) kinase cascade as especially attractive targets. Although significant issues remain with regard to the discovery of truly selective kinase inhibitors, the risks that accompany inhibition of fundamental signal transduction mechanisms can potentially be decreased by careful dissection of the pathways and rational target selection.

Figure 1

Effect of the IKK2 inhibitor, SPC839, in rat adjuvant arthritis. Rats were immunised with complete Freund's adjuvant and treated with either vehicle or the IKK2 inhibitor SPC839 (100 mg/kg/day beginning on day 15). The experiment was ended on day 28. Paw swelling (A) was determined by water displacement plethysmometry and radiographic damage (B) was determined using a semiquantitative scoring system (maximum score=6). Clinical arthritis and radiographic damage were significantly decreased by the IKK2 inhibitor. Data adapted from reference 10.

Figure 2

MAP kinase pathways. Complex parallel and interlocking signalling cascades link the three main MAP kinase families, ERK, JNK, and p38. The top level shows the MAP kinase kinase kinases (MAP3Ks), and the second tier shows the MAP kinase kinases (MAPKKs). MKK4 can also activate p38 under some circumstances.

Figure 3

Components of the JNK signalling complex. A JNK signalling complex, or signalsome, facilitates the phosphorylation of threonine and tyrosine on JNK by MKK4 and MKK7. The activated complex can then phosphorylate c-Jun on two sites and markedly increase the transcriptional activity of AP1.