TLR-mediated signals in a variety of inflammatory cells, including dendritic cells, macrophages, neutrophils, and nonhematopoietic cells, result in the production of proinflammatory cytokines. These cytokines initiate various systemic responses and "acute-phase reactions," which are characterized by altered protein expression profiles in hepatocytes, including the production of many serum proteins, suggesting that the liver is a sensor of inflammation.
Interleukin-7 (IL-7), which is known to be important for T cell homeostasis, is mainly produced by stromal cells. It is believed that the production of IL-7 in stromal cells occurs at a constant rate in vivo and is unaffected by most extrinsic stimuli. IL-7 expression in vivo, which appears to limit the size of the lymphocyte pool, is thought to be regulated by IL-7 receptor α (IL-7Rα)-mediated consumption rather than the rate of IL-7 expression. We, however, showed that excessive IL-6 signaling increased the amount of IL-7 expression in vivo, which was followed by the development of autoimmune arthritis.

Results and Discussion

We show that IL-7, the production of which was thought to occur at a constant rate in vivo, was a hepatically expressed protein that directly controled T cell responses. Depletion of IL-7 expression in the liver abrogated several TLR-mediated T cell events, including enhanced CD4+ T cell and CD8+ T cell survival, augmented CD8+ T cell cytotoxic activity, and the development of experimental autoimmune encephalitis, a Th17 cell-mediated autoimmune disease. Thus, T cell responses are regulated by hepatocyte-derived IL-7, which is expressed in response to TLR signaling in vivo. We suggested that TLR-induced IL-7 expression in the liver, which is an acute-phase response, may be a good diagnostic and therapeutic target for efficient vaccine developments and for conditions characterized by TLR-mediated T cell dysregulation, including autoimmune diseases.

Article

Contact:

Masaaki Murakami & Toshio Hirano
Laboratory of Developmental Immunology,
Graduate School of Frontier Biosciences, Graduate School of Medicine,
WPI Immunology Frontier Research Center, Osaka University,
JST, CREST

2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
Tel: +81-6-6879-3881, Fax: +81-6-6879-3889
murakami@molonc.med.osaka-u.ac.jp