Model Organisms in Drug Discovery

A CASE STUDY FOR INNATE IMMUNITY 173
Figure 6.6 A ‘simplified’ model of Rel signal transduction in Drosophila innate immune
responses. The Toll to Dif and the PGRP-LC to Relish transduction pathways are
depicted. The Toll receptor is activated by fungi and Gram-positive bacteria, leading to
degradation of Cactus, which is an IkB molecule that inhibits Dif by cytoplasmic
sequestration. The activated Dif will induce gene expression of Drosomycin. The PGRP-LC
receptor is activated by Gram-negative bacteria, which leads to endoproteolytic cleavage of
the Relish protein between the IkB and Rel domains, thereby releasing the Rel domain to
induce gene expression of CecropinA1
An immune response in S2 cells can be induced by lipopolysaccharide
(LPS) – a Gram-negative bacterial cell wall component – to express a subset
of AMPs (Han and Ip, 1999). In our experiments (Figure 6.7) and others
(Silverman et al., 2000; Sun et al., 2002), the RNAi knock-down of Relish
shows decreasing transcriptional activation of AMPs, in this case CecropinA1.
This result demonstrates that LPS activation of CecropinA1 requires the Rel
protein Relish and parallels the in vivo response of Relish mutants. In
contrast, RNAi of the IkB homolog Cactus, an inhibitor of Rel proteins Dif
and Dorsal, causes significant upregulation of the fungal response gene
Drosomycin, independent of activation. To compare the RNAi effect with the
drug effect we used parthenolide, the active component of the antiinflammatory
medicinal herb Feverfew (Tanacetun parthenium), which is
known to inhibit NF-kB signaling. Recent biochemical results suggest that the