Down-modulation of Type 1 Interferon Responses by Receptor Cross-competition for a Shared Jak Kinase

Abstract

In contrast to the large number of class I and II cytokine receptors, only four Janus kinase (Jak) proteins are expressed in mammalian cells, implying the shared use of these kinases by many different receptor complexes. Consequently, if receptor numbers exceed the amount of available Jak, cross-interference patterns can be expected. We have engineered two model cellular systems expressing two different exogenous Tyk2-interacting receptors. A receptor chimera was generated wherein the extracellular part of the interferon type 1 receptor (Ifnar1) component of the interferon-␣/␤ receptor is replaced by the equivalent domain of the erythropoietin receptor. Despite Tyk2 activation, erythropoietin treatment of cells expressing this erythropoietin receptor/Ifnar1 chimera did not evoke any detectable IFN-type response. However, a dose-dependent interference with signal transduction via the endogenous Ifnar complex was found for STAT1, STAT2, STAT3, Tyk2, and Jak1 activation, for gene induction, and for antiviral activity. In a similar approach, cells expressing the ␤1 chain of the interleukin-12 receptor showed a reduced transcriptional response to IFN-␣ as well as reduced STAT and kinase activation. In both model systems, titration of the Tyk2 kinase away from the Ifnar1 receptor chain accounts for the observed cross-interference.Members of the class I and class II cytokine receptor families are expressed on the cell surface of virtually all cell types in higher vertebrates. These receptors and their ligands are part of the complex intercellular communication network regulating essential functions, including host defense, hematopoiesis, and metabolism. The cytokine receptor subunits are composed of an extracellular ligand-binding domain containing evolutionarily conserved receptor module(s), one transmembrane domain, and a cytoplasmic region (1, 2). The mode of receptor complex formation is very heterogeneous and can be either homomeric or heteromeric. Examples of the former are the receptors for erythropoietin (Epo), 1 growth hormone, and leptin. Alternatively, ligands may induce the assembly of heteromeric receptor complexes, which are often characterized by the use of shared components: ␤c for the IL-3/IL-5/granulocyte macrophage-colony-stimulating factor group and ␥c or gp130 for the IL-2 and IL-6 families, respectively (3). More complex patterns of receptor clustering have also been reported, though there is no evidence so far for receptor complexes composed of both class I and class II subunits. Cytokine receptors lack intrinsic kinase activity, but the ligand-induced clustering or reorganization of the subunits leads to trans-phosphorylation and activation of the associated tyrosine kinases of the Jak family (4, 5). These latter kinases phosphorylate tyrosine residues in the receptor tails, allowing recruitment and activation of signaling molecules. Among these, STATs (signal transducers and activators of transcription) play an essential role in the transmission of signals to the nucleus (6).Class I and class I...

Loss of Type I IFN Receptors and Impaired IFN Responsiveness During Terminal Maturation of Monocyte-Derived Human Dendritic Cells

“…The finding that LPS-stimulated DCs rapidly and transiently produce type I IFNs and that their maturation in the presence of a mixture of neutralizing Abs directed to IFN-␣ and IFN-␤ only partially restored IFNAR1 expression suggests that ligand-mediated receptor internalization/degradation is one of the mechanisms involved in the regulation of receptor expression during DC maturation. Although IFNAR1 down-modulation cannot be explained by a reduced Tyk2 expression in LPS-mDCs, as Tyk2 levels did not change upon LPS stimulation (data not shown), a reduced intracellular availability of Tyk2 for IFNAR1, due to competition with other cytokine receptor chains interacting with Tyk2, cannot be excluded (29). Notably, the expression of IFNAR1 and IFNAR2 appears to be independently regulated in this cellular model.…”

“…Moreover, we have previously reported that IFNAR1 expression is regulated in human monocytes/macrophages by differentiation-dependent post-transcriptional mechanism(s) at least in part involving intracellular sequestration of receptor components (19), and more recently, an increase in type I IFN receptor binding sites has been observed upon in vitro differentiation of CD34 ϩ cells (27). Finally, a role for the receptor-associated Tyk2 tyrosine kinase in sustaining IFNAR1 expression has been demonstrated (28,29). The finding that LPS-stimulated DCs rapidly and transiently produce type I IFNs and that their maturation in the presence of a mixture of neutralizing Abs directed to IFN-␣ and IFN-␤ only partially restored IFNAR1 expression suggests that ligand-mediated receptor internalization/degradation is one of the mechanisms involved in the regulation of receptor expression during DC maturation.…”

Cancer Cell-derived Exosomes Induce Mitogen-activated Protein Kinase-dependent Monocyte Survival by Transport of Functional Receptor Tyrosine Kinases

“…ERK, NFB-p50, JAK1, and AKT are key survival mediators, which are activated in response to inflammation and have previously been shown to inhibit caspase activation and promote monocyte differentiation (27)(28)(29)(30). Therefore, we examined the activation of these potential survival molecules by Western blotting.…”

Association of the IFNAR1-17470 and IL-10-592 cytokine variants with susceptibility to chronic hepatitis B viral infections in a Chinese population

“…It has been demonstrated that cell surface IFNAR1 expression levels directly affect the efficiency of IFN-α-induced activity (Dondi et al, 2001). The corresponding IFNAR1 gene is situated on chromosome 21q22.11.…”