Linking microbial infections to chronic inflammation and cancer.

Clinical studies indicate a link between cancer and infectious agents as well as chronic inflammatory disorders. It is thought that infectious agents or inflammatory disorders lead to activation of NF-κB, resulting in production of growth and survival factors that stimulate cancer. Thus, activation of NF-κB seems to cause inflammation-induced tumour growth and progression.

Signalling through the mammalian tumour necrosis factor receptor 1 (TNFR1) results in activation of NF-κB. Intriguingly, TNFR1-signalling triggers the recruitment of c-IAP1 and c-IAP2, two mammalian members of the IAP protein family. Although IAPs were originally identified as inhibitor of apoptosis proteins, recent evidence suggest that IAPs also fulfil functions that operate independently of their ability to control caspases and cell death. Thus, c-IAP1 and c-IAP2, through their ability to bind to TNFR1, TRAF2 and RIP1 are implicated in modulating TNFR1 signalling and hence NF-κB. However, due to redundancy or compensatory mechanisms among these IAPs, the role of these c-IAPs in TNFR1-signalling and NF-κB activation is not clear. In contrast, in Drosophila, where redundancy is less problematic, we have identified DIAP2 as a crucial component of the immune deficiency (Imd)-signalling pathway, a NF-κB-dependent pathway that shares striking similarities with the one of mammalian TNFR1. Our studies show that DIAP2 is essential for NF-κB-mediated activation of the innate immune system of Drosophila. We are using DIAP2 as a model system to gain a better understanding of how c-IAP1 and c-IAP2 might regulate NF-κB activation in mammals.