Researchers at Weill Cornell Medical College in New York City have identified a pair of genes that may be key to the production of an immune system cytokine called interleukin-10 (IL-10), and may also have implications for research into Lupus, Cancer and HIV/AIDS.
The study, led by Dr. Xiaojing Ma, Professor of Immunology and Microbiology in the Departments of Microbiology and Immunology and Pediatrics at Weill Cornell, may fill an important "missing link" in a biochemical pathway linked to disorders ranging from lupus and Type 1 diabetes, to cancer and AIDS.
"IL-10 production has to be kept in a delicate balance for health. Too much IL-10 can leave the body more vulnerable to killers such as viruses and cancer, and to certain antibody-driven autoimmune diseases such as lupus, while too little can lead to run-away inflammatory pathology," explained Dr. Ma.
He added: "Therefore, a better understanding of IL-10 regulation moves us closer to understanding these illnesses and—potentially—how to better treat them."
Millions of body's cells undergo naturally programmed cell death every second through a process called apoptosis.
In those who are healthy, these dead cells are detected and then quickly ingested and discarded through immune system "scavenger" cells such as macrophages.
So, macrophages express the IL-10 cytokine in the presence of apoptotic cells in order to avoid this clean-up from triggering a wider immune response.
IL-10 suppresses the activity of immune system T-cells that might otherwise run amuck, Dr. Ma explained.
"That can be a good thing, of course. But on the other hand, when immune system T-cell activity is weakened too much, that can help encourage AIDS in those infected with HIV. Also, excessive T-cell suppression can keep the immune system from destroying rogue cancer cells in people battling malignancy," he said.
He added that the study results imply that "anything that we can learn about IL-10 production—and related T-cell suppression—is a boon to medical research."
Previous studies have shown that CD36 (a protein receptor lying on the surface of the macrophage) was vital in detecting apoptotic cells by macrophages.
However, in this work, CD36 was observed to be helpful in triggering IL-10 production whenever apoptotic cells were around.
This led the team to a deeper question: "What signals lead to IL-10 production from CD36 present at the cell surface?"
In order to find that out, macrophages were exposed to apoptotic (dying) cells at first, following which sensitive assays were used to find key biochemical changes occurring downstream of CD36 activation.
"We found proteins in the cell nucleus that were binding to a site we knew was critical for the production of IL-10 as macrophages encountered apoptotic cells," said Dr. Ma.
Through further experiments, the researchers identified the two genes - pre-B transcription factor 1(Pbx-1) and Pbx-regulating protein 1 (Prep-1) - responsible for the transcription (gene-directed production) of these proteins.
These genes are best known to scientists as partners for their role in embryonic development and several forms of leukemia, with Pbx playing a major part in hematopoeisis, the production of new and myriad blood cell types.
"In that sense, their presence as immune system transcription factors came as a big surprise to us. In fact, we still haven't figured out exactly how Pbx-1 and Prep-1 are involved in regulating IL-10 transcription. I really hope this study opens up new avenues for immunologists to find out whether there's a brand new biochemical pathway to be discovered," Said Dr. Ma.
The findings could also reveal exciting new information as to how aberrant IL-10 expression contributes to disease.
The study is published in the latest issue of Immunity.