Suppressor of Cytokine Signaling (SOCS)-1 in the Cell Nucleus – A Regulator of Local Immunity in the Lung?

Immune responses are tightly regulated to ensure for effective defense of pathogens but to avoid excessive bystander damage. We focus on suppressor of cytokine signaling (SOCS) 1, an inducible negative feedback inhibitor of JAK/ STAT signaling that is localized in the cell nucleus. To study the role of nuclear Socs1, a BAC transgenic mouse model has been established, expressing only non-nuclear Socs1 (Socs1ΔNLS) termed Socs1^-/- Socs1 MGL^tg. Socs1^-/- Socs1 MGL^tg mice are rescued from early lethality as compared to Socs1^-/- mice, which die due to excessive interferon signaling within three weeks after birth. Classical interferon gamma signaling in bone-marrow derived macrophages is not altered in Socs1^-/- Socs1 MGL^tg mice as shown by phosphorylation of STAT1 and by regulation of classical interferon gamma target genes. Microarray analysis verified those results but revealed differential expression of a subset of non-classical interferon gamma target genes in mice lacking nuclear Socs1. Although cytoplasmic Socs1 is crucial for survival, Socs1^-/- Socs1 MGL^tg mice slowly develop inflammatory lesions and eosinophilia in the lung and a low-grade steatohepatitis, arguing for local immune regulatory functions of nuclear Socs1. Taken together, Socs1^-/- Socs1 MGL^tg mice present a valuable tool to study the nuclear function of Socs1 in vivo.