Toll receptors: an expanding role in our understanding of human disease

Toll receptor proteins in Drosophila are involved in establishing the dorsa l-ventral axis in embryogenesis as well as participating in the innate immu ne response to invading pathogens. The basic mediators of this response sho w striking similarities in plants, insects, and vertebrates. The cytoplasmi c signaling cascade is exemplified by the human interleukin-1 receptor comp lex (IL-1R), resulting in transcriptional activation of effector proteins t hrough nuclear factor-KB (NF-KB), Six mammalian/human Toll-like receptors ( TLR) have been described to date. The TLRs share the IL-1R cytoplasmic sign aling cascade but are distinguished by their extracellular leucine-rich rep eat (LRR) structure, The LRR superfamily comprises a diverse group of prote ins, including a cohort involved in transmembrane signaling. Two of the hum an TLRs (TLR2, TLR4) have been shown to be involved in the innate response to bacterial pathogens and appear to provide a link between the innate and adaptive immune response. A better understanding of this response may provi de improved therapeutic modalities in the treatment of bacterial and fungal sepsis, which continues to be a significant source of morbidity and mortal ity worldwide. In addition, similar to Drosophila, Toll receptors and relat ed proteins in the LRR superfamily may also be involved in human developmen t, as well as in noninfectious human disease.