Interaction of IL-10 with IL-10R1 variants

Interleukin-10 (IL-10) is a regulatory protein that is secreted from immune cells during active inflammation. It is thought to counteract inappropriate inflammation by inducing a series of anti-inflammatory effects in the body. Animal models with IL-10 deficiency exhibit chronic inflammation of the bowel similar to human Crohn`s disease, indicating that IL-10 regulates the immune response in the gut. All IL-10 induced signals are conducted over interaction of IL-10 with IL-10 receptor 1 (IL-10R1). We previously identified genetic variants of the IL-10R1, so called single nucleotide polymorphisms (SNP), SNP3 and SNP4. The worldwide distribution of these variants had been studied in 51 native populations. Both were most common in Semites and Caucasians (up to half of the population) and absent in Asians or Native Americans. These receptor variants changed the cellular response to IL-10.We also found that these variants protect individuals from development of some diseases but confer susceptibility to others supporting the notion that these genetic variations in the IL-10R1 are biologically relevant. Inhere we propose to study the molecular mechanisms behind our previous observations. By using standard biochemical methods, we will investigate the differential interaction of IL-10 and the IL-10R1 variants SNP3 and SNP4. Our research will help to better understand the impact of genetic variations on the cause of chronic inflammatory disease.

Approximately every 1000 base pairs, the human DNA carries a variation at a single base pair, a so called single nucleotide polymorphisms (SNP). Most of these variations are irrelevant; however, some change the sequence of amino acids and potentially the function of the protein: for example, certain SNPs determine the color of hair or eyes. In this project we studied the functional relevance of certain mutations within the interleukin-10 receptor 1 (IL10R1). This receptor is a key molecule of the mammalian immune system that binds human IL-10 but also IL- 10 homolog proteins, which are expressed after certain viral infections (e.g. by cytomegalovirus). We had previously identified two variants on the IL10R1, which are commonly found in Caucasians and are associated with or protect from various disease phenotypes (as studied in the preceding project P15314). Here we show that the extracellular receptor variant (an exchange of the amino acid serine to glycine at position 138) reduces receptor function and signal transduction by about 50%. Interestingly, this receptor variant almost completely abolishes the ability of virus-derived IL-10 to utilize this receptor indicating that during viral infection the variant IL10R1 provides advantage to the host.