The role of A20 in the regulation of NF-kappaB and myeloid homeostasis.

摘要

The mammalian immune system has evolved to recognize virtually any microbial pathogens its host may encounter. In reaction to microbial pathogens, the host elicits an inflammatory response. Inflammation represents an early response to infection with the intent of eliminating the pathogen and preventing its spread. This process is characterized by the production of pro-inflammatory mediators that are toxic to the pathogen, as well as potentially the host. Thus, in order to preserve host integrity, the process of inflammation requires strict regulation.;Cells of the innate immune system, which include myeloid lineage cells, function as sentinels by detecting microbial pathogens via toll-like receptors (TLRs). TLRs directly recognize microbial pathogens or components derived from them, such as gram-negative bacterial lipopolysaccharide (LPS). TLR signaling results in the activation of the transcription factor nuclear factor-kappaB (NF-kappaB). Active NF-kappaB drives the transcription and translation of pro-inflammatory gene products, including tumor necrosis factor (TNF) which is critical for potentiating the inflammatory process. TNF acts on many cell types to promote the process of inflammation via further activation of NF-kappaB.;A20 is an NF-kappaB-dependent novel zinc finger protein that when overexpressed can abolish the activation of NF-kappaB by multiple stimuli. TNF-treated mice induce A20 mRNA in numerous tissues indicating that it functions in multiple cell types and tissues. To further study the function of A20 in vivo , mice deficient in A20 were generated by gene targeting. A20-deficient (A20-/-) mice exhibit spontaneous multi-organ inflammation, cachexia, and die prematurely. This inflammation is characterized by accumulation of myeloid lineage cells (granulocytes and macrophages). Adoptive transfer of A20-/- or A20-/- RAG1-/- fetal livers results in aberrant accumulation of myeloid lineage cells in multiple tissues of chimeric mice, illuminating a cell autonomous role for A20 in regulating myeloid homeostasis. In response to TNF or LIPS A20-/- cells appropriately activate NF-kappaB, but fail to terminate this response resulting in prolonged activation of NF-kappaB. Thus, A20 is required to terminate NF-kappaB activation in response to TNF or LPS.;Taken together, these studies demonstrate a required role for A20 in proper regulation of NF-kappaB activation and inflammation in vivo .