| Reference | 1. J Immunol. 2011 Nov 1;187(9):4611-20. doi: 10.4049/jimmunol.1100649. Epub 2011
Sep 28.
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Pyridone 6, a pan-JAK inhibitor, ameliorates allergic skin inflammation of NC/Nga
mice via suppression of Th2 and enhancement of Th17.
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Nakagawa R(1), Yoshida H, Asakawa M, Tamiya T, Inoue N, Morita R, Inoue H, Nakao
A, Yoshimura A.
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Author information: <br>
(1)Department of Microbiology and Immunology, Keio University School of Medicine,
Shinjuku-ku, Tokyo 160-8582, Japan.
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Atopic dermatitis (AD) is a common pruritic inflammatory disease triggered by a
defective skin barrier and immunodysregulation. AD has been considered a typical
example of a Th2 response associated with allergic disease. In the early phases
of the disease, symptoms include IgE hyperproduction, eosinophil accumulation,
and mast cell activation; in the chronic phase, a Th1-dominant immune response is
also observed at the sites of AD skin lesions. The role of IL-17-producing Th
(Th17) cells in AD has not been established. In the current study, we found that
pyridone 6 (P6), a pan-JAK inhibitor, delayed the onset and reduced the magnitude
of skin disease in an AD-like skin-disease model of NC/Nga mice. P6 reduced IFN-γ
and IL-13, whereas it enhanced IL-17 and IL-22 expression. In vitro, P6 also
inhibited both Th1 and Th2 development, whereas it promoted Th17 differentiation
from naive T cells when present within a certain range of concentrations. This
was probably because P6 strongly inhibited STAT1, STAT5, and STAT6
phosphorylation, whereas STAT3 phosphorylation was less efficiently suppressed by
P6 at the same concentration. Furthermore, IL-22 protects keratinocytes from
apoptosis induced by IFN-γ, and administration of IL-17 and IL-22 partially
ameliorated skin diseases in NC/Nga mice. These results suggested that the JAK
inhibitor P6 is therapeutic for AD by modulating the balance of Th2 and Th17.
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2. Biochem Biophys Res Commun. 2011 Jan 7;404(1):261-7. doi:
10.1016/j.bbrc.2010.11.104. Epub 2010 Nov 25.
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Effects of a Janus kinase inhibitor, pyridone 6, on airway responses in a murine
model of asthma.
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Matsunaga Y(1), Inoue H, Fukuyama S, Yoshida H, Moriwaki A, Matsumoto T,
Matsumoto K, Asai Y, Kubo M, Yoshimura A, Nakanishi Y.
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Author information: <br>
(1)Research Institute for Diseases of the Chest, Graduate School of Medical
Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
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Th2 cytokines and their downstream Janus kinase (JAK)-signal transducer and
activation of transcription (STAT) pathways play a critical role in allergic
asthma. We studied the effects of a pan-JAK inhibitor, pyridone 6 (P6), on
asthmatic responses in a mouse model and investigated the mechanism for its
biological effects. Mice were sensitized and challenged by ovalbumin (OVA). P6
treatment during the challenge phase suppressed eosinophilia in bronchoalveolar
lavage (BAL) fluids but did not affect airway hyperresponsiveness (AHR). To
improve the efficacy of the JAK inhibitor, P6 was encapsulated in
polylactic-coglycolic acid nanoparticles (P6-PLGA). P6-PLGA treatment just before
OVA challenge suppressed both airway eosinophilia and AHR. Although the IL-13
levels in BAL fluids and the OVA-specific IgE levels in serum after the challenge
phase treatment with P6-PLGA were similar to those after a sham treatment, the
eotaxin levels in BAL fluids and lung mCLCA3/Gob-5 expression were decreased in
P6-PLGA-treated mice. Interestingly, the local IL-13 levels and serum
OVA-specific IgE were decreased, while IL-17-producing T cells were increased by
P6-PLGA treatment during the sensitization plus challenge phases. In vitro, P6
strongly suppressed the differentiation of Th2 from naive CD4 T cells, but it
partly enhanced Th17 differentiation. P6 potently suppressed IL-13-mediated STAT6
activation and mCLCA3/Gob-5 expression in mouse tracheal epithelial cells. These
findings suggest that the JAK inhibitor P6 suppresses asthmatic responses by
inhibiting Th2 inflammation and that application of PLGA nanoparticles improves
the therapeutic potency of P6.
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3. Biol Pharm Bull. 2009 Jan;32(1):45-50.
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Pyridone 6, a pan-Janus-activated kinase inhibitor, suppresses osteoclast
formation and bone resorption through down-regulation of receptor activator of
nuclear factor-kappaB (NF-kappaB) ligand (RANKL)-induced c-Fos and nuclear factor
of activated T cells (NFAT) c1 expression.
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Kwak HB(1), Kim HS, Lee MS, Kim KJ, Choi EY, Choi MK, Kim JJ, Cho HJ, Kim JW, Bae
JM, Kim YK, Park BH, Ha H, Chun CH, Oh J.
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Author information: <br>
(1)Department of Anatomy, Wonkwang University, Jeonbuk, Korea.
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It has been reported that Janus tyrosine kinase (JAK)-dependent signaling
pathways play a critical role in the pathogenesis of numerous malignancies and
immune reactions, and inhibition of JAK has been implicated in cell growth
inhibition. The role which JAK has on osteoclast differentiation and anti-bone
resorptive activity is not well understood. In this study, we investigated the
effects of a pan-JAK inhibitor, pyridone 6, on osteoclast differentiation and
bone-resorption in vitro and ex vivo. Pyridone 6 inhibited osteoclast
differentiation in mouse bone marrow macrophage (BMM) cultures stimulated by the
receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) and
co-cultures of bone marrow cells and osteoblasts. Pyridone 6 suppressed the
expression of c-Fos and nuclear factor of activated T cells (NFAT) c1 in BMMs. It
also inhibited the bone resorptive activity of mature osteoclasts that was
accompanied by disruption of actin rings. Pyridone 6 also suppressed I-kappaB
degradation and extracellular signal-regulated kinase (ERK) in mature
osteoclasts, suggesting that these are the key molecules that pyridone 6 targets
in the inhibition of osteoclast function. These results demonstrate inhibition of
JAK may be useful for the treatment of bone-resorptive diseases, such as
osteoporosis.
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4. Cancer Res. 2006 Oct 1;66(19):9714-21.
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Pyridone 6, a pan-Janus-activated kinase inhibitor, induces growth inhibition of
multiple myeloma cells.
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Pedranzini L(1), Dechow T, Berishaj M, Comenzo R, Zhou P, Azare J, Bornmann W,
Bromberg J.
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Author information: <br>
(1)Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY
10021, USA.
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Interleukin-6 (IL-6) and the subsequent Janus-activated kinase (JAK)-dependent
signaling pathways play a critical role in the pathogenesis of multiple myeloma.
Here, we compared the sensitivity and specificity of a novel pan-JAK inhibitor,
tetracyclic pyridone 6 (P6), with that of AG490 in a panel of myeloma-derived
cell lines. P6 induced growth arrest and subsequent apoptosis of the
IL-6-dependent hybridoma and myeloma-derived cell lines (B9 and INA-6) grown
either in IL-6-containing medium or in the presence of bone marrow-derived
stromal cells (BMSC) using much lower concentrations of drug and with
significantly faster kinetics than AG490. Myeloma-derived cell lines, which
either express constitutively activated JAK/signal transducers and activators of
transcription (STAT) 3 (U266) or are IL-6 growth stimulated (KMS11), are
partially growth inhibited by P6. However, P6 does not inhibit the growth of
myeloma-derived cell lines lacking activated JAKs/STATs nor does it inhibit
mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK)
kinase activity compared with AG490, which led to activation of ERK and induced
robust apoptosis of all the examined cell lines. Finally, P6 inhibited the growth
of primary myeloma patient samples grown in the presence of BMSCs. Thus, P6 is a
more sensitive and specific inhibitor of JAK-STAT3 activity compared with AG490
and potently inhibited the growth of primary myeloma cells and myeloma-derived
cell lines grown on BMSCs.
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