June 2014

Alternative p38 MAPKs Are Essential for Collagen-Induced Arthritis

Arthritis and Rheumatology Vol66, No. 5, May2014 pp 1208-1217

MAPK family proteins are regulatory proteins, affecting processes such as synthesis and release of proinflammatory molecules which contribute to the pathogenesis of RA. In particular, the p38 MAPK protein family is central to proinflammatory cytokine production. There are four member of the p38 group; p38α, p38β, p38γ and p38δ. This study sought to evaluate p38γ and p38δ deficiency in mice CIA model. In p38γ-/- or p38δ-/- mice, the percentage of mic...

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Mechanism of Activation of Protein Kinase JAK2 by the Growth Hormone Receptor

Science 344, 2014; doi: 10.1126/science.1249783

Class I cytokine receptors are key regulators of many processes within the body. The receptors use the JAK-STAT signalling pathway, the deregulation of which causes it to become an important pathway in oncogenesis. Despite this, the processes responsible for JAK2 activation by class I receptors remains elusive. Previous studies using growth hormone and its receptor have led to a model of receptor activation where hormone induced receptor dimerization resulted in close proximity of the receptor i...

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Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition

Proc Natl Acad Sci U S A. 2014 May 19. pii: 201401180. [Epub ahead of print]

The JAK family of kinases (JAK1, JAK2, JAK3 and TYK2) are receptor-associated tyrosine kinases that act downstream of many cytokines and interferons. Recent studies have provided structural information about the kinase and pseudokinase domains of JAKs however the molecular mechanism by which JAK activity is regulated by the pseudokinase domain is poorly understood. This study builds on a recent finding that the N terminus of the JAK1 pseudokinase group may act as a switch for kinase activation b...

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Structural basis for the recognition of interferon-α receptor by tyrosine kinase 2

Nat Struct Mol Biol. 2014 May;21(5):443-8. doi: 10.1038/nsmb.2807. Epub 2014 Apr 6

Janus kinases, JAKs, are essential in the mediation of cytokine and interferon signalling whilst also being crucial to body processes such as immune function, hematopoeises, metabolism and cellular growth. However, it is not known is how the four members of the JAK family interact with and are activated by over 30 cytokine receptors with near perfect affinity and specificity. Currently, there are no crystal structures available for any JAK bound to a cytokine receptor. This study sought address ...

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May 2014

JAK2-STAT3 Blockade by AG490 Suppresses Autoimmune Arthritis in Mice via Reciprocal Regulation of Regulatory T cells and Th17 cells

J Immunol 2014; 192:4417-4424

In this study, Park et al sought to investigate the effects of the JAK2 inhibitor, AG490 in RA. Using murine CIA models, both preventative and therapeutic models were investigated. In the preventative model, CIA mice treated with AG490 showed a significantly lower incidence rate of arthritis and arthritic scores when compared to mice injected with vehicle. In the therapeutic model, as in the preventative, AG490 treated mice exhibited less severe arthritis. Through further experiments, it was dem...

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Blocking the janus-activated kinase pathway reduces tumor necrosis factor alpha-induced interlukin-18 bioactivity by caspase-1 inhibition

Arthritis Research and Therapy 2014,16:R102

IL-18, a member of the IL-1 family, has been shown to play an important role in immune response and is involved in the pathogenesis of RA. The study objective was to examine the role of the JAK pathway in modulating TNFa-induced-IL18 bioactivity by reducing caspase-1 function. Caspase-1 is the protease that cleaves pro-IL-18 to IL-18, thereby activating it. In testing it was noted that by blocking the JAK pathway significantly decreased caspase-1 transcription, expression and activity showing th...

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Btk inhibition suppresses agonist-induced human macrophage activation and inflammatory gene expression in RA synovial tissue explants

Ann Rheum Dis Published Online First 24 April 2014 doi:10.1136/annrheumdis-2013-204143

Bruton’s tyrosine kinase, a downstream target of PI3K signalling, has been shown to be crucial in the B lymphocyte and myeloid cell contribution to murine models of arthritis. Synovial tissue samples were taken from biologically naïve RA (n=16) and PsA (n=12) patients in order to assess the expression of BTK. Separate RA synovial explants (n=8) were used to assess the effects of the specific BTK inhibitor RN486. BTK was expressed at equivalent levels in both RA and PsA synovial tissue, however e...

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14-3-3eta is a novel mediator associated with the pathogenesis of rheumatoid arthritis and joint damage

Arthritis Research and Therapy 2014, 16:R99

A major clinical imperative among rheumatologists is the ability to class patients into risk categories for radiographic progression. Indeed, identification of new independent biomarkers predictive of RA disease progression is a key target from OMERACT. This study by Maksymowych et al. sought to clarify the role of 14-3-3? in RA and whether it provided any clinically and/or serologically important prognostic information. First described as being elevated in RA in 2007, 14-3-3? has a strong corre...

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April 2014

Effects of Janus Kinase Inhibitor tofacitinib on circulating serum amyloid A and interlukin-6 during treatment for rheumatoid arthritis

Clinical and Experimental Immunology doi.10.1111/cei.12234

Tofacitinib is a JAK inhibitor currently approved for the treatment of RA in some parts of the world. In this paper, Migita et al tested the effects of tofacitinib on circulating serum amyloid A (SAA). SAA is a major acute-phase reactant in RA and studies have shown it may be a better marker for the assessment of inflammatory joint disease compared with C-reactive protein. SAA is induced by the binding of IL-6 and the activation of the JAK/STAT pathway, which is inhibited by tofacitinib. Results...

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Hypoxia and STAT3 signalling interactions regulate pro-inflammatory pathways in rheumatoid arthritis

. ARD published online first 13 Feb 2014. Doi: 10.1136/annrheumdis-2013-204105

Hypoxia is a key driving force in joint inflammation, however little is known about the effect it can have on JAK/STAT signalling in rheumatoid arthritis. Due to the development of JAK inhibitors as therapeutics it is important to understand any links there may be. Previous studies have shown that HIF1a, a protein associated with hypoxia, facilitates the binding of STAT3 to haptoglobin promoter in HepG2 human hepatoma cells. HIF1a also requires interaction of Notch signalling pathways with STAT3...

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