The role of SOCS1 in the cell nucleus - Regulation of local immunity in the lung?

Suppressor of Cytokine Signaling 1 (SOCS1) is a negative feedback inhibitor of cytoplasmic Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling pathways. In 2008, it has been shown that SOCS1 contains a nuclear localization sequence (NLS) resulting in translocation of the protein into the cell nucleus. The exact function of SOCS1 in the cell nucleus remains largely unknown. To study the role of SOCS1 in the cell nucleus in vivo, a transgenic mouse model was established using a bacterial artificial chromosome (BAC) containing a mutated Socs1 locus with non-nuclear Socs1deltaNLS, GFP and firefly Luciferase, termed MGL. C57BL/6 mice expressing only non-nuclear Socs1deltaNLS were bred by back-crossing Socs1MGLtg mice on a SOCS1 deficient background and named Socs1-/-MGLtg mice. Nonnuclear Socs1deltaNLS was shown to rescue those mice from the early lethal phenotype observed in Socs1-/- mice. Interferon gamma (IFNg) signaling was analyzed by Western Blot, fow cytometry, quantitative real-time PCR and whole-genome expression analysis. Socs1-/-MGLtg mice showed functional regulation of canonical IFNg signaling - a function classically attributed to cytoplasmic SOCS1. Only a small subset of non-canonical, IFNg dependent genes was differentially regulated. In contrast, Socs1-/-MGLtg mice showed altered cell cycle regulation as well as sustained NFkB signaling - two functions suggested to be dependent on SOCS1 in the cell nucleus. Socs1-/-MGLtg mice spontaneously developed a Th2 prone low-grade inflammation in the lung including elevated serum IgE levels and low-grade airway eosinophilia. Influx of eosinophils could be enhanced both in an experimental asthma model using ovalbumin and upon IL-13 instillation. Bone-marrow transplantation experiments indicated an important role for radiation-resistant cells in the development of the allergic phenotype in Socs1-/-MGLtg mice. Therefore, epithelial cells were investigated in more detail. Reduced epithelial cell barrier integrity was observed both in vivo by the detection of albumin in BAL and in vitro using primary murine trachea epithelial cells (pmTECs). In summary, Socs1-/-MGLtg mice were used to study the role of nuclear SOCS1. Nuclear SOCS1 was shown to be an important regulator of local immunity in the lung and to exert a so-far unrecognized function in epithelial cells