Janus kinase (JAK) enzymes are involved in cell signaling pathways activated by various cytokines dysregulated in allergy. The objective of this study was to determine whether the novel JAK inhibitor oclacitinib could reduce the activity of cytokines implicated in canine allergic skin disease. Using isolated enzyme systems and in vitro human or canine cell models, potency and selectivity of oclacitinib was determined against JAK family members and cytokines that trigger JAK activation in cells. Oclacitinib inhibited JAK family members by 50% at concentrations (IC50's) ranging from 10 to 99 nm and did not inhibit a panel of 38 non-JAK kinases (IC50's > 1000 nm). Oclacitinib was most potent at inhibiting JAK1 (IC50 = 10 nm). Oclacitinib also inhibited the function of JAK1-dependent cytokines involved in allergy and inflammation (IL-2, IL-4, IL-6, and IL-13) as well as pruritus (IL-31) at IC50's ranging from 36 to 249 nm. Oclacitinib had minimal effects on cytokines that did not activate the JAK1 enzyme in cells (erythropoietin, granulocyte/macrophage colony-stimulating factor, IL-12, IL-23; IC50's > 1000 nm). These results demonstrate that oclacitinib is a targeted therapy that selectively inhibits JAK1-dependent cytokines involved in allergy, inflammation, and pruritus and suggests these are the mechanisms by which oclacitinib effectively controls clinical signs associated with allergic skin disease in dogs.
We have produced an Fc conjugate of colony-stimulating factor (CSF) 1 with an
improved circulating half-life. CSF1-Fc retained its macrophage growth-promoting
activity, and did not induce proinflammatory cytokines in vitro.
Treatment with CSF1-Fc did not produce adverse effects in mice or pigs. The
impact of CSF1-Fc was examined using the Csf1r-enhanced green
fluorescent protein (EGFP) reporter gene in MacGreen mice. Administration of
CSF1-Fc to mice drove extensive infiltration of all tissues by
Csf1r-EGFP positive macrophages. The main consequence was
hepatosplenomegaly, associated with proliferation of hepatocytes. Expression
profiles of the liver indicated that infiltrating macrophages produced candidate
mediators of hepatocyte proliferation including urokinase, tumor necrosis
factor, and interleukin 6. CSF1-Fc also promoted osteoclastogenesis and produced
pleiotropic effects on other organ systems, notably the testis, where
CSF1-dependent macrophages have been implicated in homeostasis. However, it did
not affect other putative CSF1 targets, notably intestine, where Paneth cell
numbers and villus architecture were unchanged. CSF1 has therapeutic potential
in regenerative medicine in multiple organs. We suggest that the CSF1-Fc
conjugate retains this potential, and may permit daily delivery by injection
rather than continuous infusion required for the core molecule.
The fibrinolytic potential of the vasculature is modulated primarily by the availability and activity of plasminogen activators, which convert the zymogen plasminogen into the active fibrin-degrading enzyme plasmin. The activities of these key regulatory enzymes are directly neutralized by their primary endogenous inhibitor, plasminogen activator inhibitor-1 (PAI-1). Although some individuals with a tendency to develop thrombotic disorders exhibit elevated levels of PAI-1 in their plasma, the cause-and-effect relationship between increased PAI-1 and thrombosis is still unclear. Specifically, it is not known whether chronic depression of fibrinolytic activity results in the development of thrombosis. To address this question we developed transgenic mice in which the contribution of PAI-1 to thrombus formation could be evaluated. The results presented in this report indicate that elevated levels of PAI-1 contribute to the development of venous but not arterial occlusions.
Background -Interleukin-31 (IL-31) is a member of the gp130 ⁄ interleukin-6 cytokine family that is produced by cell types such as T helper 2 lymphocytes and cutaneous lymphocyte antigen positive skin homing T cells. When overexpressed in transgenic mice, IL-31 induces severe pruritus, alopecia and skin lesions. In humans, IL-31 serum levels correlate with the severity of atopic dermatitis in adults and children.Hypothesis ⁄ Objective -To determine the role of IL-31 in canine pruritus and naturally occurring canine atopic dermatitis (AD).Animals -Purpose-bred beagle dogs were used for laboratory studies. Serum samples were obtained from laboratory animals, nondiseased client-owned dogs and client-owned dogs diagnosed with naturally occurring AD.Methods -Purpose-bred beagle dogs were administered canine interleukin-31 (cIL-31) via several routes (intravenous, subcutaneous or intradermal), and pruritic behaviour was observed ⁄ quantified via video monitoring. Quantitative immunoassay techniques were employed to measure serum levels of cIL-31 in dogs.Results -Injection of cIL-31 into laboratory beagle dogs caused transient episodes of pruritic behaviour regardless of the route of administration. When evaluated over a 2 h period, dogs receiving cIL-31 exhibited a significant increase in pruritic behaviour compared with dogs that received placebo. In addition, cIL-31 levels were detectable in 57% of dogs with naturally occurring AD ( ‡13 pg ⁄ mL) but were below limits of quantification (<13 pg ⁄ mL) in normal, nondiseased laboratory or client-owned animals.Conclusions -Canine IL-31 induced pruritic behaviours in dogs. Canine IL-31 was detected in the majority of dogs with naturally occurring AD, suggesting that this cytokine may play an important role in pruritic allergic skin conditions, such as atopic dermatitis, in this species.
We have identified a novel -hydroxy-alkanedicarboxylic acid, ESP 55016, that favorably alters serum lipid variables in obese female Zucker (fa/fa) rats. ESP 55016 reduced serum non-HDL-cholesterol (non-HDL-C), triglyceride, and nonesterified fatty acid levels while increasing serum HDL-C and  -hydroxybutyrate levels in a dose-dependent manner. ESP 55016 reduced fasting serum insulin and glucose levels while also suppressing weight gain. In primary rat hepatocytes, ESP 55016 increased the oxidation of
Highlights► The active region of porcine CSF-1 and full length CSF-1R have been cloned. ► Biological activity of porcine CSF-1 has been demonstrated. ► The cross species reactivity of IL-34 has been investigated. ► Both mouse and human IL-34 are biologically active on the pig CSF-1R. ► CSF-1 and IL-34 structure analysis of species-specific activity has been performed.
Recent studies indicating that some nonsteroidal anti-inflammatory drugs (NSAIDs) selectively modulate gamma-secretase cleavage of amyloid precursor protein (APP) while sparing Notch processing have generated interest in discovery of novel gamma-secretase modulators with the "NSAID-like" efficacy profile. The objective of the present studies was to compare the efficacy of a subset of NSAIDs with previously reported classical gamma-secretase inhibitors LY-411575 [N(2)-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N(1)-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide]and DAPT [N-[N- (3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester] in Tg2576 mice. Flurbiprofen (10 and 25 mg/kg/day) was overtly toxic and elicited significant (but nonselective) reductions in both Abeta(1-40) and Abeta(1-42) in the plasma in one of two studies. Flurbiprofen also produced a small reduction in Abeta(1-40) in the cortex at 25 mg/kg/day but did not affect Abeta levels in hippocampus or cerebrospinal fluid. Ibuprofen and sulindac sulfide were neither overtly toxic nor efficacious at doses up to 50 mg/kg/day. The effects of NSAIDs LY-411575 and DAPT were tested in guinea pig embryonic neuronal cultures to determine whether the selective reductions in Abeta(1-42) observed in cell lines overexpressing human mutant APP can be reproduced in a neuronal model of physiological Abeta production and secretion. Flurbiprofen and sulindac nonselectively reduced Abeta(1-40) and Abeta(1-42) at concentrations > or =125 microM, although cytotoxicity was noted at > or =250 microM sulindac. Ibuprofen had no effect at concentrations up to 500 microM. In contrast, DAPT and LY-411575 potently and completely inhibited Abeta(1-40), Abeta(1-42), and Abeta(1-38) in the absence of cytotoxicity. The divergence of the present data from published reports raises the need to examine the conditions necessary to perceive selective Abeta(1-42) reduction by NSAIDs in neuronal tissue.
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