Role of Tyk-2 in Th9 and Th17 cells in allergic asthma

Übel, Caroline; Graser, Anna; Koch, Stefan; Rieker, Ralf J.; Lehr, Hans A.; Müller, Mathias; Finotto, Susetta

doi:10.1038/srep05865

Cited by 29 publications

(21 citation statements)

References 47 publications

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“…Activation of STAT1 by treatment of naïve mouse T cells cultured under T H 9 cell-inducing conditions with IFNγ dramatically suppressed IL-9 production by reducing the sensitivity of these cells to IL-4 1 . In an asthma model, deficiency in Tyk2, the Janus kinase required for type I IFN signalling and STAT1 activation, resulted in increased IL-9 production 29 . In an experimental autoimmune encephalomyelitis (EAE) model system, IFNγ induced IL-27 production by dendritic cells (DCs) that suppressed T H 9 cell differentiation both in vivo and in vitro in a STAT1 and T-bet-dependent manner 30 .…”

Section: Regulation Of Th9 Cell Developmentmentioning

confidence: 99%

The development and in vivo function of T helper 9 cells

2015

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The specialized cytokine secretion profiles of T helper (TH) cells are the basis for a focused and efficient immune response. On the 20th anniversary of the first descriptions of cytokine signals that act to differentiate interleukin-9 (IL-9)-secreting T cells, this review focuses on the extracellular signals and transcription factors that promote the development of what we now term TH9 cells, which are characterized by the production of this cytokine. We summarize our current understanding of the contribution of TH9 cells to both effective immunity and immunopathological disease and propose that TH9 cells could be targeted for the treatment of allergic and autoimmune disease.

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Section: Regulation Of Th9 Cell Developmentmentioning

confidence: 99%

The development and in vivo function of T helper 9 cells

2015

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“…Tyk2-deficient mice display reduced responses to IFN␣/␤ and IL-12 and a deficiency in STAT3 activation (26). The Tyk2/STAT3 axis has also been implicated in the induction of neuronal death in Alzheimer disease (27), as a biomarker for Crohn's disease (28), and in controlling allergic asthma (29). Marrero et al (30) first showed that angiotensin II (Ang II) induces Tyk2 activation in rat aortic smooth muscle cells, a finding verified in other studies (31)(32)(33)(34).…”

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confidence: 99%

Regulation of Connexin43 Function and Expression by Tyrosine Kinase 2

Spagnol

et al. 2016

Journal of Biological Chemistry

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Gap junctions are integral membrane proteins that enable the direct cytoplasmic exchange of ions and low molecular weight metabolites (Ͻ1 kDa) between adjacent cells. They provide an intercellular pathway for the propagation and/or amplification of signal transduction cascades triggered by cytokines, growth factors, and other cell-signaling molecules involved in growth regulation and development. Gap junctions are formed by the apposition of connexons from adjacent cells, where each connexon is formed by six connexin proteins. Connexins are tetraspanning transmembrane proteins with intracellular N and C termini (CT). 2 There are 21 human isoforms, and although there is significant sequence homology among connexins, their major divergence occurs in the cytoplasmic domains. Connexin43 (Cx43), the most ubiquitously expressed connexin isoform, has been well studied in terms of structure, function, and regulation (1).Cx43 channels can be regulated by a variety of molecules and physiological conditions (e.g. Ca 2ϩ , pH, and intercellular voltage), including through phosphorylation (2, 3). All stages of the Cx43 life cycle (i.e. trafficking, assembly/disassembly, degradation, and channel gating (3)), as well as the regulation of electrical and metabolic coupling and of interactions with other proteins, involve phosphorylation. The Cx43CT is differentially phosphorylated on at least 20 residues, and significant progress has been achieved in characterizing the kinases involved (2, 4 -6). Unfortunately, an understanding of the mechanism(s) by which Cx43 phosphorylation alters channel function is lacking. Several problems contributing to this difficulty include the transient nature of a particular CT phosphorylation state, the ability of many kinases to phosphorylate more than one CT residue, the ability of various kinases to phosphorylate the CT at the same time, and the inability to precisely control which residues are phosphorylated. Strategies employed to overcome these difficulties include the use of phospho-specific CT antibodies (7) and short CT phosphopeptides (8, 9). Also well appreciated is the use of Asp (or Glu) substitutions as a mimetic for phosphorylation (10, 11).The negative charge of the phosphate could affect the permeability of ions through the pore, alter the structure of the transmembrane ␣-helices to influence pore size, or modify the binding affinities of molecular partners involved in Cx43 regulation. Notably, if phosphorylation modifies protein interactions to affect the kinetics of channel assembly/disassembly or degradation, cell-to-cell communication will also be altered. Evidence has emerged that a phosphate can directly block the Cx43CT interaction with ZO-1 (9) and tubulin (8) or enhance the interaction with Nedd4 (12, 13). This information is critical because a particular cellular condition can be correlated with a specific Cx43 phosphorylation status to understand which proteins will and will not interact to affect regulation of Cx43. Numerous serine protein kinases have been identified as...

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“…Tyk2-deficient mice are highly susceptible to viral, bacterial, and parasitic infections, which are mainly due to a diminished type I IFN response and an impaired IL-12-dependent IFN-g production (1). Owing to their altered Th1/Th2, Th9, and Th17 cytokine profiles, these mice are more prone to allergic airway inflammation (2,3). Alternatively, Tyk2-null mice are more resistant to autoimmune diseases (4,5).…”

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confidence: 99%

Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis

Hainzl

Stockinger

Rauch

et al. 2015

The Journal of Immunology

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In the intestinal tract, IL-22 activates STAT3 to promote intestinal epithelial cell (IEC) homeostasis and tissue healing. The mechanism has remained obscure, but we demonstrate that IL-22 acts via tyrosine kinase 2 (Tyk2), a member of the Jak family. Using a mouse model for colitis, we show that Tyk2 deficiency is associated with an altered composition of the gut microbiota and exacerbates inflammatory bowel disease. Colitic Tyk2−/− mice have less p-STAT3 in colon tissue and their IECs proliferate less efficiently. Tyk2-deficient primary IECs show reduced p-STAT3 in response to IL-22 stimulation, and expression of IL-22–STAT3 target genes is reduced in IECs from healthy and colitic Tyk2−/− mice. Experiments with conditional Tyk2−/− mice reveal that IEC-specific depletion of Tyk2 aggravates colitis. Disease symptoms can be alleviated by administering high doses of rIL-22–Fc, indicating that Tyk2 deficiency can be rescued via the IL-22 receptor complex. The pivotal function of Tyk2 in IL-22–dependent colitis was confirmed in Citrobacter rodentium–induced disease. Thus, Tyk2 protects against acute colitis in part by amplifying inflammation-induced epithelial IL-22 signaling to STAT3.

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Role of Tyk-2 in Th9 and Th17 cells in allergic asthma

Cited by 29 publications

References 47 publications

The development and in vivo function of T helper 9 cells

The development and in vivo function of T helper 9 cells

Regulation of Connexin43 Function and Expression by Tyrosine Kinase 2

Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis

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