Therapeutic Targeting of the JAK/STAT Pathway Aittomäki, Saara; Pesu, Marko
Basic & clinical pharmacology & toxicology,
January 2014, Letnik:
114, Številka:
1
Journal Article, Conference Proceeding
Recenzirano
Antibodies that block cytokine function provide a powerful therapeutic tool especially for the treatment of autoimmune diseases. Cytokines are a group of small hydrophilic glycoproteins that bind ...their receptors on the cell surface and subsequently activate intracellular signalling cascades, such as the JAK/STAT pathway. A bulk of evidence has demonstrated that genetic mutations in signalling molecules can cause immunodeficiencies and malignant cell growth. As a result, several drug companies have begun to develop therapeutics that inhibit the function of JAK tyrosine kinases. Currently, two JAK inhibitors, tofacitinib and ruxolitinib, are used in the clinic for treating rheumatoid arthritis and myeloproliferative diseases, respectively. Inhibiting JAK function has been shown to efficiently prevent the uncontrolled growth of cancerous cells and to harness overly active immune cells. In the future, other small molecule compounds are likely to come into clinical use, and intense work is ongoing to develop inhibitors that specifically target the constitutively active mutant JAKs. This MiniReview will summarize the basic features of the JAK/STAT pathway, its role in human disease and the therapeutic potential of JAK/STAT inhibitors.
Abstract
The aim of this study was to evaluate the effects of deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) on systemic inflammatory responses in patients with ...drug-resistant epilepsy (DRE). Twenty-two Finnish patients with ANT-DBS implantation were enrolled in this pilot study. Changes in plasma interleukin-6 (IL-6) and interleukin-10 (IL-10) levels were examined using generalized estimating equation models at seven time points (before DBS surgery and 1, 2, 3, 6, 9 and 12 months after implantation). In the whole group, the IL-6/IL-10 ratio decreased significantly over time following ANT-DBS, while the decrease in IL-6 levels and increase in IL-10 levels were not significant. In the responder and nonresponder groups, IL-6 levels remained unchanged during the follow-up. Responders had significantly lower pre-DBS IL-10 levels before the ANT-DBS treatment than nonresponders, but the levels significantly increased over time after the treatment. In addition, responders had a higher pre-DBS IL-6/IL-10 ratio than nonresponders, and the ratio decreased for both groups after treatment, but the decrease did not reach the level of statistical significance. The rate of decrease in the ratio per month tended to be higher in responders than in nonresponders. These results may highlight the anti-inflammatory properties of ANT-DBS treatment associated with its therapeutic effectiveness in patients with DRE. Additional studies are essential to evaluate the potential of the proinflammatory cytokine IL-6, the anti-inflammatory cytokine IL-10, and their ratio as biomarkers to evaluate the therapeutic response to DBS treatment, which could facilitate treatment optimization.
Antibodies against glutamic acid decarboxylase (GADA) are present in multiple neurological manifestations, such as stiff-person syndrome, cerebellar ataxia, limbic encephalitis, and epilepsy. ...Increasing data support the clinical significance of GADA as an autoimmune etiology of epilepsy, however, there is not yet definitive evidence to confirm the pathogenic link between GADA and epilepsy.
Interleukin-6 (IL-6), a pro-convulsive and neurotoxic cytokine, and interleukin-10 (IL-10), an anti-inflammatory and neuroprotective cytokine, are crucial inflammatory mediators in the brain. Increased production of IL-6 and its association with epileptic disease profiles are well established, suggesting the presence of chronic systemic inflammation in epilepsy. Therefore, in this study, we investigated the association of plasma cytokine concentrations of IL-6 and IL-10 and their ratio with GADA in patients with drug-resistant epilepsy.
Interleukin-6 and IL-10 concentrations were measured by ELISA in plasma, and the IL-6/IL-10 ratio was calculated in a cross-sectional cohort of 247 patients with epilepsy who had their GADA titers measured previously for their clinical significance in epilepsy. Based on GADA titers, patients were grouped as GADA negative (
= 238), GADA low positive (antibody titers < 1,000 RU/mL,
= 5), and GADA high positive (antibody titers ≥ 1,000 RU/mL,
= 4).
Median IL-6 concentrations were significantly higher in patients with high GADA positivity 2.86 pg/mL, interquartile range (IQR) = 1.90-5.34 pg/mL than in GADA-negative patients 1.18 pg/mL, interquartile range (IQR) = 0.54-2.32 pg/mL;
= 0.039. Similarly, IL-10 concentrations were also higher in GADA high-positive patients 1.45 pg/mL, interquartile range (IQR) = 0.53-14.32 pg/mL than in GADA-negative patients 0.50 pg/mL, interquartile range (IQR) = 0.24-1.00 pg/mL, however, the difference was not statistically significant (
= 0.110). Neither IL-6 nor IL-10 concentrations were different between GADA-negative and GADA low-positive patients (
> 0.05) or between GADA low-positive or GADA high-positive patients (
> 0.05). The IL-6/IL-10 ratio was also similar among all the study groups.
Increased circulatory concentrations of IL-6 are associated with high GADA titers in patients with epilepsy. These data provide additional pathophysiological significance of IL-6 and help to further describe the immune mechanisms involved in the pathogenesis of GADA-associated autoimmune epilepsy.
Summary
Cytokines play pivotal roles in immunity and inflammation, and targeting cytokines and their receptors is an effective means of treating such disorders. Type I and II cytokine receptors ...associate with Janus family kinases (JAKs) to effect intracellular signaling. These structurally unique protein kinases play essential and specific roles in immune cell development and function. One JAK, JAK3, has particularly selective functions. Mutations of this kinase underlie severe combined immunodeficiency, indicative of its critical role in the development and function of lymphocytes. Because JAK3 appears not to have functions outside of hematopoietic cells, this kinase has been viewed as an excellent therapeutic target for the development of a new class of immunosuppressive drugs. In fact, several companies are developing JAK3 inhibitors, and Phase II studies are underway. Mutations of Tyk2 cause autosomal recessive hyperIgE syndrome, and in principle, Tyk2 inhibitors might also be useful as immunosuppressive drugs. JAK2 gain‐of‐function mutations (V617F) underlie a subset of disorders collectively referred to as myeloproliferative diseases and phase 2 trials using JAK inhibitors are underway in this setting. Thus, we are learning a great deal about the feasibility and effectiveness of targeting Janus kinases, and it appears likely that this will be a fruitful strategy in a variety of settings.
Therapeutic options for psoriasis vulgaris have changed during recent decades with the introduction of biologics. Few nationwide studies are available on psoriasis treatment patterns, and those from ...Finland predate the use of biologics. The aim of this retrospective, population-based registry study was to identify patients with psoriasis vulgaris and their treatment patterns in the secondary care setting in Finland. The study cohort included 41,456 adults with a diagnosis of psoriasis vulgaris in the public secondary healthcare setting from 2012 through 2018. Data on comorbidities, pharmacotherapy, and phototherapy were collected from nationwide healthcare and drug registries. Patients in the cohort had a wide range of comorbidities, with 14.9% having psoriatic arthritis. Treatment was based largely on topical and conventional systemic medications. Conventional medications were used by 28.9% of patients, and methotrexate was the most common option (20.9%). Biologics were used by 7.3% of patients, mostly as second- and third-line treatment. The use of conventional systemic medications, topical treatments, and phototherapy decreased after the initiation of biologics. This study of psoriasis vulgaris in Finland provides a framework for the development of future care practices.
Abstract
Background
Increasing evidence supports the role of soluble inflammatory mediators in the pathogenesis of refractory temporal lobe epilepsy (TLE). Hippocampal sclerosis (HS) is a ...well-described pathohistological abnormality in TLE. The association of proinflammatory cytokines with epileptic disease profiles is well established; however, the potential significance of circulating interleukin 10 (IL-10), particularly in TLE-associated HS, is still poorly understood. Therefore, taking into consideration the neuroprotective and anticonvulsive effects of IL-10, we performed this study to examine the role of the plasma levels of IL-10 in patients with TLE with HS (TLE + HS), TLE without HS (TLE-HS) and with other types of epilepsy.
Methods
This study included 270 patients with refractory epilepsy who were classified into four groups: i) 34 patients with TLE + HS, ii) 105 patients with TLE-HS, iii) 95 patients with extra-TLE (XLE) and iv) 36 patients with idiopathic generalized epilepsy (IGE). The plasma IL-10 levels were quantified using a commercially available enzyme-linked immunosorbent assay (ELISA).
Results
IL-10 levels were significantly lower in TLE + HS than in TLE-HS (
p
= 0.013). In a subgroup of TLE-HS patients who had seizures 1 month before sampling, patients with seizures had significantly higher IL-10 levels than patients who were seizure-free (
p
= 0.039). Among a small group (
n
= 15) of non-refractory TLE-HS patients, IL-10 levels showed a moderate negative correlation with the duration of epilepsy (
r
= − 0.585,
p
= 0.023).
Conclusions
This study demonstrated that chronically reduced levels of plasma IL-10 were associated with HS in TLE patients, suggesting that there was an inadequate systemic anti-inflammatory immune response. These results could provide new biological insights into the pathophysiology of HS in TLE. We also found that the production of IL-10 could be affected by the seizure frequency and declined concomitantly with increased disease durations. Therefore, the measurement of plasma IL-10 may have diagnostic value as a biomarker for stratifying TLE + HS from other epilepsy types or as a marker of disease progression towards a progressive form of epilepsy.
The proprotein convertase enzyme FURIN promotes the proteolytic maturation of pro-proteins and thereby it serves as an important factor for maintaining cellular homeostasis. In T cells, FURIN is ...critical for maintaining the T regulatory cell dependent peripheral immune tolerance and intact T helper cell polarization. The enzymatic activity of FURIN is directly associated with its expression levels, but genetic determinants for cell-type specific
gene regulation have remained elusive. By exploring the histone acetyltransferase p300 binding patterns in T helper cells, a putative regulatory region at ca. 20kB upstream of
gene was identified. When this region was deleted with CRISPR/Cas9 the production of
mRNA was significantly reduced in activated mouse T cells. Genome-wide RNA profiling by sequencing revealed that the novel
regulator region also impacted the expression of several genes that have previously been associated with the Th1 type hall mark cytokine IFNγ regulation or function. Finally,
genetic regulatory region was found to specifically promote the secretion of IFNγ by activated T cells. In sum, our data unravels the presence of
expression regulatory region in T cells that has characteristics of a super-enhancer for Th1 cell fate.
Members of the substilisin/kexin like proprotein convertase (PCSK) protease family cleave and convert immature
pro-proteins into their biologically active forms. By cleaving for example prohormones, ...cytokines and cell membrane
proteins, PCSKs participate in maintaining the homeostasis in a healthy human body. Conversely, erratic enzymatic function
is thought to contribute to the pathogenesis of a wide variety of diseases, including obesity and hypercholestrolemia.
The first characterized seven PCSK enzymes (PCSK1-2, FURIN, PCSK4-7) process their substrates at a motif made up of
paired basic amino acid residues. This feature results in a variable degree of biochemical redundancy in vitro, and consequently,
shared substrate molecules between the different PCSK enzymes. This redundancy has confounded our understanding
of the specific biological functions of PCSKs. The physiological roles of these enzymes have been best illustrated
by the phenotypes of genetically engineered mice and patients that carry mutations in the PCSK genes. Recent developments
in genome-wide methodology have generated a large amount of novel information on the genetics of the first
seven proprotein convertases. In this review we summarize the reported genetic alterations and their associated phenotypes.
Hip arthroplasty is the standard treatment of a painful hip destruction. The use of modern metal-on-metal (MOM) bearing surfaces gained popularity in total hip arthroplasties during the last decade. ...Recently, worrisome failures due to adverse reaction to metal debris (ARMD), including pseudotumor response, have been widely reported. However, the pathogenesis of this reaction remains poorly understood. The aim of the present study was to investigate the ARMD response by flow cytometry approach.
Sixteen patients with a failed Articular Surface Replacement (ASR) hip prosthesis were included in the study. Samples of pseudotumor tissues collected during revision surgery were degraded by enzyme digestion and cells were typed by flow cytometry. Whole blood chromium and cobalt concentrations were analyzed with mass spectrometry before revision surgery.
Flow cytometry analysis showed that the peri-implant pseudotumor tissue expressed two principal phenotypes, namely macrophage-dominated and T-lymphocyte-dominated response; the average portions being 54% (macrophages) and 25% (T-lymphocytes) in macrophage-dominated inflammation and 20% (macrophages) and 54% (T-lymphocytes) in T-lymphocyte-dominated response. The percentages of B-lymphocytes and granulocytes were lower in both phenotypes. Interestingly, the levels of blood chromium and cobalt were significantly higher in patients with macrophage-dominated response.
The results suggest that the adverse tissue reactions induced by MOM wear particles contain heterogeneous pathogeneses and that the metal levels are an important factor in the determination of the inflammatory phenotype. The present results support the hypothesis that higher metal levels cause cytotoxicity and tissue injury and macrophages are recruited to clear the necrotic debris. On the other hand, the adverse response developed in association with lower metal levels is T-lymphocyte-dominated and is likely to reflect hypersensitivity reaction.
Intestinal microfold cells (M cells) are a dynamic lineage of epithelial cells that initiate mucosal immunity in the intestine. They are responsible for the uptake and transcytosis of microorganisms, ...pathogens, and other antigens in the gastrointestinal tract. A mature M cell expresses a receptor Gp2 which binds to pathogens and aids in the uptake. Due to the rarity of these cells in the intestine, their development and differentiation remain yet to be fully understood. We recently demonstrated that polycomb repressive complex 2 (PRC2) is an epigenetic regulator of M cell development, and 12 novel transcription factors including Atoh8 were revealed to be regulated by the PRC2. Here, we show that Atoh8 acts as a regulator of M cell differentiation; the absence of Atoh8 led to a significant increase in the number of Gp2+ mature M cells and other M cell-associated markers such as Spi-B and Sox8. In vitro organoid analysis of RankL treated organoid showed an increase of mature marker GP2 expression and other M cell-associated markers. Atoh8 null mice showed an increase in transcytosis capacity of luminal antigens. An increase in M cell population has been previously reported to be detrimental to mucosal immunity because some pathogens like orally acquired prions have been able to exploit the transcytosis capacity of M cells to infect the host; mice with an increased population of M cells are also susceptible to
infections. Our study here demonstrates that PRC2 regulated Atoh8 is one of the factors that regulate the population density of intestinal M cell in the Peyer's patch.
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