Dr. Auron's interests in the relationship between molecular structure and function have guided his work. Most studies have focused on mechanistic approaches that often rely upon correlation with known high-resolution structures and molecular model building. Dr. Auron has also contributed to the bioinformatics field, having published several papers dealing with nucleic acid analysis software and hardware. Two commercial software packages aimed at molecular biology users have resulted from his efforts. The research focuses on molecular mechanisms of cytokine gene regulation. One of these cytokines is interleukin 1 (IL-1) which influences genes expressing various proteins that can modulate the level of acute and chronic inflammation and thus mediate subsequent fever and tissue destruction. In 1984, Dr. Auron was involved in the original cloning and characterization of IL-1beta cDNA. This was followed by the isolation and sequencing of the corresponding IL1B gene locus. The induced IL1B gene product is involved in inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, arteriosclerosis, bacterial sepsis and infection by certain viruses. The laboratory has placed emphasis on the detailed molecular processes and structures involved both in receptor signal transduction and gene transcription in normal cells and those expressing proinflammatory proteins derived from cytomegalovirus infection. Attention has also been paid to cell-type-specific expression. As a result, Dr. Auron and his collaborators have determined that the monomyeloid-specific ETS domain transcription factor, Spi-1/PU.1, is required for vigorous expression of the IL1B gene. They have also determined that physical interaction between Spi-1 and GATA-family proteins is responsible for a mutual inhibition that is critical for stem cell commitment to erythroid vs. mono-myeloid lineage development in hematopoiesis. Spi-1, which is essential for monocyte and osteoclast development, binds to the IL1B gene and couples the gene induction signal, found in a distinct location approximately 3kbp upstream from the transcription start site, directly to the general transcription machinery. The Spi-1/PU.1 factor is also targeted during human cytomegalovirus (HCMV) infection and mediates viral-induction of IL1B by eliminating the requirement for the exogenous activation signal via one specific HCMV protein (IE2, immediate early protein 2). Research focusing on receptor signal transduction has resulted in the discovery that the IL-1 receptor-activated intracellular signal transducer called TRAF6 functions through at least two distinct pathways that result in differential activation of Rel/NF-kappaB transcription factor family members. This may be responsible for some of the known subtleties of the inflammatory response.