Conditional ablation of TYK2 in immunity to viral infection and tumor surveillance.

Tyrosine kinase 2 (TYK2) has a pivotal role in immunity to infection and tumor surveillance. It is associated with several cytokine receptor chains including type I interferon (IFN) receptor 1 (IFNAR1), interleukin- (IL-) 12 receptor beta 1 (IL-12Rb1) and IL-10R2. We have generated a mouse with a conditional Tyk2 null allele and proved integrity of the conditional Tyk2 locus.

TYK2 kinase activity is required for functional type I interferon responses in vivo.

Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family and is involved in cytokine signalling. In vitro analyses suggest that TYK2 also has kinase-independent, i.e.

Tristetraprolin-driven regulatory circuit controls quality and timing of mRNA decay in inflammation.

For a successful yet controlled immune response, cells need to specifically destabilize inflammatory mRNAs but prevent premature removal of those still used. The regulatory circuits controlling quality and timing in the global inflammatory mRNA decay are not understood. Here, we show that the mRNA-destabilizing function of the AU-rich element-binding protein tristetraprolin (TTP) is inversely regulated by the p38 MAPK activity profile such that after inflammatory stimulus the TTP-dependent decay is initially limited to few mRNAs.

Generation of mice with a conditional Stat1 null allele.

Interferons (IFNs) are key cytokines in the innate immune response that also bridge the gap to adaptive immunity. Signaling upon stimulation by IFN type I, II and III is mediated by the Jak-Stat pathway. STAT1 is activated by all three IFN receptor complexes and absence of STAT1 from mice increases their susceptibility to pathogens.

Organ-specific and differential requirement of TYK2 and IFNAR1 for LPS-induced iNOS expression in vivo.

Lipopolysaccharide (LPS) is an integral structural component of the outer membrane of Gram-negative bacteria and the principal active agent in the pathogenesis of endotoxin shock. LPS is a potent inducer of a variety of cytokines and inflammatory agents that lead to a profound alteration of gene expression patterns in cells and organs. The gene coding for the inducible nitric oxide synthase (iNOS) is highly responsive to LPS in vitro and in vivo and accounts for the production of nitric oxide (NO).