scholarly journals IL-23 Enhances C-Fiber-Mediated and Blue Light-Induced Spontaneous Pain in Female Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Jasmine Ji ◽  
Qianru He ◽  
Xin Luo ◽  
Sangsu Bang ◽  
Yutaka Matsuoka ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Blue Light ◽  
Inflammatory Diseases ◽  
Intrathecal Injection ◽  
Spontaneous Pain ◽  
Dependent Manner ◽  
Intraplantar Injection ◽  
Nociceptive Neurons ◽  
Female Mice ◽  
C Fiber

The incidence of chronic pain is especially high in women, but the underlying mechanisms remain poorly understood. Interleukin-23 (IL-23) is a pro-inflammatory cytokine and contributes to inflammatory diseases (e.g., arthritis and psoriasis) through dendritic/T cell signaling. Here we examined the IL-23 involvement in sexual dimorphism of pain, using an optogenetic approach in transgenic mice expressing channelrhodopsin-2 (ChR2) in TRPV1-positive nociceptive neurons. In situ hybridization revealed that compared to males, females had a significantly larger portion of small-sized (100-200 μm2) Trpv1+ neurons in dorsal root ganglion (DRG). Blue light stimulation of a hindpaw of transgenic mice induced intensity-dependent spontaneous pain. At the highest intensity, females showed more intense spontaneous pain than males. Intraplantar injection of IL-23 (100 ng) induced mechanical allodynia in females only but had no effects on paw edema. Furthermore, intraplantar IL-23 only potentiated blue light-induced pain in females, and intrathecal injection of IL-23 also potentiated low-dose capsaicin (500 ng) induced spontaneous pain in females but not males. IL-23 expresses in DRG macrophages of both sexes. Intrathecal injection of IL-23 induced significantly greater p38 phosphorylation (p-p38), a marker of nociceptor activation, in DRGs of female mice than male mice. In THP-1 human macrophages estrogen and chemotherapy co-application increased IL-23 secretion, and furthermore, estrogen and IL-23 co-application, but not estrogen and IL-23 alone, significantly increased IL-17A release. These findings suggest a novel role of IL-23 in macrophage signaling and female-dominant pain, including C-fiber-mediated spontaneous pain. Our study has also provided new insight into cytokine-mediated macrophage-nociceptor interactions, in a sex-dependent manner.

Fentanyl decreases discharges of C and A nociceptors to suprathreshold mechanical stimulation in chronic inflammation

2012 ◽  
Vol 108 (10) ◽  
pp. 2827-2836 ◽  
Author(s):  
Rabih Moshourab ◽  
Christoph Stein
Keyword(s):  
Chronic Inflammation ◽  
Tissue Injury ◽  
Mechanical Hyperalgesia ◽  
Acute Injury ◽  
Dependent Manner ◽  
Mechanical Stimuli ◽  
Nociceptive Neurons ◽  
C Fibers ◽  
C Fiber ◽  
Inflamed Tissue

An essential component of mechanical hyperalgesia resulting from tissue injury is an enhanced excitability of nociceptive neurons, termed mechanical sensitization. Local application of opioids to inflamed rat paws attenuates mechanical hyperalgesia and reduces electrical excitability of C-fiber nociceptors in acute injury. Here, we examined the effects of the opioid receptor agonist fentanyl on the mechanical coding properties of not only C- but also A-fiber nociceptors innervating the rat hind paw in a model of chronic pain, i.e., 4 days after Freund's complete adjuvant-induced inflammation. The peripheral mechanosensitive terminals of C-fibers ( n = 143), A-fibers ( n = 79), and low-threshold mechanoreceptors ( n = 25) were characterized using the in vitro skin-nerve preparation from the saphenous nerve. Although mechanical activation thresholds were not changed, discharges to suprathreshold mechanical stimuli were elevated significantly in both A- and C-fiber nociceptors from inflamed tissue. In addition, the proportion of nociceptors as well as the frequency of spontaneous discharges in A (14% vs. 0%)- and C (28% vs. 8%)-fibers were increased in inflamed compared with normal tissue. Fentanyl inhibited responses to suprathreshold stimuli in a significantly higher proportion of not only C (36% vs. 7%)- but also A (41% vs. 8%)-fibers in inflamed tissue in a naloxone-reversible and concentration-dependent manner. Our results demonstrate that mechanical sensitization persists in chronic inflammation, in correlation with behavioral hyperalgesia. Opioid sensitivity of both A- and C-fibers is markedly augmented. This is consistent with an upregulation or enhanced functionality of opioid receptors located at the peripheral terminals of sensitized nociceptors.

scholarly journals AB0095 PRECLINICAL CHARACTERIZATION OF CJ-15314, A HIGHLY SELECTIVE JAK1 INHIBITOR, FOR THE TREATMENT OF AUTOIMMUNE DISEASES

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1347.2-1347
Author(s):  
S. Y. Ki ◽  
H. Shin ◽  
Y. Lee ◽  
H. R. Bak ◽  
H. Yu ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Autoimmune Diseases ◽  
Whole Blood ◽  
Inflammatory Diseases ◽  
Selective Inhibition ◽  
Janus Kinase ◽  
Dependent Manner ◽  
Human Whole Blood

Background:Janus kinases (JAK1, JAK2, JAK3, and TYK2) play critical roles in mediating various cytokine signaling, and has been developed as a target for autoimmune diseases such as RA. Tofacitinib, oral Pan-JAK inhibitor, demonstrated efficacy in RA patients, but its widespread use is limited by safety issues. Baricitinib, JAK1/2 inhibitor, is also known to interfere with the hematopoiesis system, such as anemia and thrombocytopenia associated with suppression of JAK2 signals. Therefore, it is necessary to develop a new potent compound that selectively inhibits JAK1 over JAK2, 3Objectives:To identify the pharmacological characteristic based on efficacy of CJ-15314 as potent and selective JAK1 inhibitor for treatment of autoimmune disease.Methods:In vitro, cell-based, kinase panel, Kd value and human whole blood assay were performed to determine the inhibition potency and selectivity for JAK subfamily kinases. In vivo therapeutic potential was evaluated by RA model including rat Adjuvant-Induced Arthritis (AIA) and collagen-induced arthritic (CIA). To confirm the possibility of further expansion into the autoimmune disease, BioMAP® Diversity PLUS® Panel was performed by discoverX.Results:In vitro assay, CJ-15314 inhibited JAK kinase family in a concentration-dependent manner with IC50 values of 3.8 nM against JAK1, Selectivity for JAK1 over JAK2, 3 was approximately 18, 83 fold greater for CJ-15314. In 1mM ATP condition, CJ-15314 has been confirmed to have the highest JAK1 selectivity over competing drugs, under 1 mM ATP condition that reflects the physiological environment in the body. Similarly, Kd values has also confirmed the selectivity of JAK1, which is 10 fold higher than JAK2, 3. Accordingly, in human whole blood assays, CJ-15314 is 11 fold more potent against IL-6 induced pSTAT1 inhibition through JAK1 (IC50 value: 70 nM) than GM-CSF-induced pSTAT5 inhibition (JAK2) whereas baricitinib and filgotinib exhibited only 2 fold and 7 fold respectively.In vivo efficacy model, CJ-15314 inhibited disease severity scores in a dose dependent manner. In the rat AIA model, CJ-15314 at 30 mg/kg dose showed 95.3% decrease in arthritis activity score, 51.2% in figotinib at 30 mg/kg, 97.7% showed baricitinib at 10 mg/kg. CJ-15314 showed superior anti-arthritic efficacy than filgotinib. CJ-15314 also minimally affected anemia-related parameters but not bricitinib end of the 2-week treatment. In the rat CIA model, like 10 mg/kg of bricitinib, 30 mg/kg of CJ-15314 also has a similar effect, with a significant reduction in histopathological scores.In biomap diversity panel, CJ-15314 inhibited the expression of genes such as MCP-1, VCAM-1, IP-10, IL-8, IL-1, sTNF-α and HLA-DR confirming the possibility of expansion into other diseases beyond arthritis.Conclusion:CJ-15314 is a highly selective JAK1 inhibitor, demonstrates robust efficacy in RA animal model and is good candidate for further development for inflammatory diseases.* CJ-15314 is currently conducting a phase I trial in south Korea.References:[1]Clark JD et al. Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J Med Chem. 2014; 57(12):5023-38.[2]Burmester GR et al. Emerging cell and cytokine targets in rheumatoid arthritis. Nat Rev Rheumatol. 2014; 10(2):77-88[3]Jean-Baptiste Telliez et al. Discovery of a JAK3-selective inhibitor: functional differentiation of JAK3-selective inhibition over pan-JAK or JAK1-selective inhibition. ACS Chem. Biol., 2016; 11 (12):3442-3451Disclosure of Interests:so young Ki Employee of: CJ healthcare, hyunwoo shin Employee of: CJ healthcare, yelim lee Employee of: CJ healthcare, Hyoung rok Bak Employee of: CJ healthcare, hana yu Employee of: CJ healthcare, Seung Chan Kim Employee of: CJ healthcare, juhyun lee Employee of: CJ healthcare, donghyun kim Employee of: CJ healthcare, Dong-hyun Ko Employee of: CJ Healthcare, dongkyu kim Employee of: CJ healthcare

scholarly journals Control of microtubule dynamics using an optogenetic microtubule plus end–F-actin cross-linker

2017 ◽  
Vol 217 (2) ◽  
pp. 779-793 ◽  
Author(s):  
Rebecca C. Adikes ◽  
Ryan A. Hallett ◽  
Brian F. Saway ◽  
Brian Kuhlman ◽  
Kevin C. Slep
Keyword(s):  
Blue Light ◽  
Actin Binding ◽  
Cross Linking ◽  
Dependent Manner ◽  
Exclusion Zone ◽  
Actin Networks ◽  
Drosophila Melanogaster S2 Cells ◽  
Actin Binding Domain ◽  
Specific Factors ◽  
Insight Into

We developed a novel optogenetic tool, SxIP–improved light-inducible dimer (iLID), to facilitate the reversible recruitment of factors to microtubule (MT) plus ends in an end-binding protein–dependent manner using blue light. We show that SxIP-iLID can track MT plus ends and recruit tgRFP-SspB upon blue light activation. We used this system to investigate the effects of cross-linking MT plus ends and F-actin in Drosophila melanogaster S2 cells to gain insight into spectraplakin function and mechanism. We show that SxIP-iLID can be used to temporally recruit an F-actin binding domain to MT plus ends and cross-link the MT and F-actin networks. Cross-linking decreases MT growth velocities and generates a peripheral MT exclusion zone. SxIP-iLID facilitates the general recruitment of specific factors to MT plus ends with temporal control enabling researchers to systematically regulate MT plus end dynamics and probe MT plus end function in many biological processes.

Neurophysiological basis for neurogenic-mediated articular cartilage anabolism alteration

2001 ◽  
Vol 280 (1) ◽  
pp. R115-R122 ◽  
Author(s):  
Elvire Gouze-Decaris ◽  
Lionel Philippe ◽  
Alain Minn ◽  
Philippe Haouzi ◽  
Pierre Gillet ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Ex Vivo ◽  
Cartilage Damage ◽  
Intrathecal Injection ◽  
Chronic Administration ◽  
C Fibers ◽  
Glutamatergic Synaptic Transmission ◽  
C Fiber ◽  
Fiber Stimulation ◽  
Neurophysiological Basis

This study was designed to investigate the pathways involved in neurogenic-mediated articular cartilage damage triggered by a nonsystemic distant subcutaneous or intra-articular inflammation. The cartilage damage was assessed 24 h after subcutaneous or intra-articular complete Freund's adjuvant (CFA) injection measuring patellar proteoglycan (PG) synthesis (ex vivo [Na2 35SO4] incorporation) in 96 Wistar rats. Unilateral subcutaneous or intra-articular injection of CFA induced significant decrease (25–29%) in PG synthesis in both patellae. Chronic administration of capsaicin (50 mg · kg−1 · day−1 during 4 days), which blunted the normal response of C fiber stimulation, prevented the bilateral significant decrease in cartilage synthesis. Similarly, intrathecal injection of MK-801 (10 nmol/day during 5 days), which blocked the glutamatergic synaptic transmission at the dorsal horn of signal originating in primary afferent C fibers, eliminated the CFA-induced PG synthesis decrease in both patellae. Chemical sympathectomy, induced by guanethidine (12.5 mg · kg−1 · day−1 during 6 wk), also prevented PG synthesis alteration. Finally, compression of the spinal cord at the T3-T5 level had a similar protective effect on the reduction of [Na2 35SO4] incorporation. It is concluded that the signal that triggers articular cartilage synthesis damage induced by a distant local inflammation 1) is transmitted through the afferent C fibers, 2) makes glutamatergic synaptic connections with the preganglionic neurons of the sympathetic system, and 3) involves spinal and supraspinal pathways.

scholarly journals Positive cross talk between protein kinase D and β-catenin in intestinal epithelial cells: impact on β-catenin nuclear localization and phosphorylation at Ser552

2016 ◽  
Vol 310 (7) ◽  
pp. C542-C557 ◽  
Author(s):  
Jia Wang ◽  
Liang Han ◽  
James Sinnett-Smith ◽  
Li-Li Han ◽  
Jan V. Stevens ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Epithelial Cells ◽  
Transgenic Mice ◽  
Nuclear Localization ◽  
Cross Talk ◽  
Intestinal Epithelial Cells ◽  
Dependent Manner ◽  
Intestinal Epithelial ◽  
Ang Ii ◽  
Potent Inducer

Given the fundamental role of β-catenin signaling in intestinal epithelial cell proliferation and the growth-promoting function of protein kinase D1 (PKD1) in these cells, we hypothesized that PKDs mediate cross talk with β-catenin signaling. The results presented here provide several lines of evidence supporting this hypothesis. We found that stimulation of intestinal epithelial IEC-18 cells with the G protein-coupled receptor (GPCR) agonist angiotensin II (ANG II), a potent inducer of PKD activation, promoted endogenous β-catenin nuclear localization in a time-dependent manner. A significant increase was evident within 1 h of ANG II stimulation ( P < 0.01), peaked at 4 h ( P < 0.001), and declined afterwards. GPCR stimulation also induced a marked increase in β-catenin-regulated genes and phosphorylation at Ser552 in intestinal epithelial cells. Exposure to preferential inhibitors of the PKD family (CRT006610 or kb NB 142-70) or knockdown of the isoforms of the PKD family prevented the increase in β-catenin nuclear localization and phosphorylation at Ser552 in response to ANG II. GPCR stimulation also induced the formation of a complex between PKD1 and β-catenin, as shown by coimmunoprecipitation that depended on PKD1 catalytic activation, as it was abrogated by cell treatment with PKD family inhibitors. Using transgenic mice that express elevated PKD1 protein in the intestinal epithelium, we detected a marked increase in the localization of β-catenin in the nucleus of crypt epithelial cells in the ileum of PKD1 transgenic mice, compared with nontransgenic littermates. Collectively, our results identify a novel cross talk between PKD and β-catenin in intestinal epithelial cells, both in vitro and in vivo.

Functional expression of a heterologous major histocompatibility complex class I gene in transgenic mice

1987 ◽  
Vol 7 (11) ◽  
pp. 4003-4009
Author(s):  
C Bieberich ◽  
T Yoshioka ◽  
K Tanaka ◽  
G Jay ◽  
G Scangos
Keyword(s):  
Major Histocompatibility Complex ◽  
Transgenic Mice ◽  
Major Histocompatibility Complex Class ◽  
Inbred Mice ◽  
Class I ◽  
Dependent Manner ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
I Gene

The regulated expression of major histocompatibility complex class I antigens is essential for assuring proper cellular immune responses. To study H-2 class I gene regulation, we have transferred a foreign class I gene to inbred mice and have previously shown that the heterologous class I gene was expressed in a tissue-dependent manner. In this report, we demonstrate that these mice expressed the transgenic class I molecule on the cell surface without any alteration in the level of endogenous H-2 class I antigens. Skin grafts from transgenic mice were rapidly rejected by mice of the background strain, indicating that the transgenic antigen was expressed in an immunologically functional form. As with endogenous H-2 class I genes, the class I transgene was inducible by interferon treatment and suppressible by human adenovirus 12 transformation. Linkage analysis indicated that the transgene was not closely linked to endogenous class I loci, suggesting that trans-regulation of class I genes can occur for class I genes located outside the major histocompatibility complex.

Abstract 382: Oxidized LDL Signaling “Primes” GPVI-Mediated Platelet Activation in a CD36-Dependent Manner

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Gabriella Kartz ◽  
Moua Yang ◽  
Andrea Sanchez ◽  
Roy Silverstein
Keyword(s):  
Signaling Pathways ◽  
Platelet Activation ◽  
Inflammatory Diseases ◽  
Oxidized Ldl ◽  
Flow Chamber ◽  
Dependent Manner ◽  
Nucleotide Exchange ◽  
Functional Link ◽  
Glycated Proteins ◽  
Platelet Accumulation

CD36 acts as an important participant in the prothrombotic state associated with chronic inflammatory diseases such as atherosclerosis and diabetes by serving as a signaling relay point for danger-associated molecular patterns (DAMPs), including oxidized low-density lipoproteins (oxLDL) and advanced glycated proteins. Although CD36-mediated signaling pathways have been well characterized in macrophages, less is known about CD36-mediated signaling in platelets. Our group identified important roles for specific Src family kinases (SFK) Lyn and Fyn, and for the guanine nucleotide exchange factors Vav1 and Vav3. Since platelet activation by the collagen receptor GPVI also involves downstream activation of SFKs, we now hypothesize that oxLDL signaling via CD36 primes platelets for hyperactivity by activating components of the GPVI signaling pathway. To test this hypothesis, we treated fluorescently labeled murine platelets with either native LDL (nLDL) or oxLDL and exposed them to immobilized collagen under defined shear flow in a microfluidic flow chamber. A significant increase (~1.2 fold) in platelet accumulation was observed with oxLDL treatment. No increase in accumulation was observed in oxLDL-treated platelets from cd36 null mice, suggesting that this phenomenon was CD36-dependent. Furthermore, addition of tirofiban ablated the oxLDL-induced increase in platelet accumulation, suggesting that the increase was likely due to enhanced platelet-platelet contacts (i.e. enhanced platelet activation). This supports previous data from our laboratory showing that treatment of murine platelets with oxLDL alone resulted in activation of αIIbβ3 integrin. Additionally, oxLDL-treated platelets from vav1/vav3 double null mice phenocopied cd36 null platelets and displayed no increase in platelet accumulation compared to nLDL-treated platelets, strengthening the functional link between CD36 and GPVI signaling pathways. These data suggest a functional link between CD36 and GPVI signaling pathways in platelets, which may contribute to platelet hyperactivity in athero-inflammatory diseases.

scholarly journals IPSE, a Parasite-Derived, Host Immunomodulatory Infiltrin Protein, Alleviates Resiniferatoxin-Induced Bladder Pain

2020 ◽  
Author(s):  
Kenji Ishida ◽  
Evaristus C. Mbanefo ◽  
Loc Le ◽  
Olivia Lamanna ◽  
Luke F. Pennington ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Analgesic Effect ◽  
Transient Receptor Potential ◽  
Nuclear Localization Sequence ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Bladder Pain ◽  
Nociceptive Neurons ◽  
Sequence Dependent ◽  
Localization Sequence

AbstractThe transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor is an important mediator of nociception and its expression is enriched in nociceptive neurons. TRPV1 signaling has been implicated in bladder pain and is a potential analgesic target. Resiniferatoxin is the most potent known agonist of TRPV1. Acute exposure of the rat bladder to resiniferatoxin has been demonstrated to result in pain-related freezing and licking behaviors that are alleviated by virally encoded IL-4. The interleukin-4-inducing principle of Schistosoma mansoni eggs (IPSE) is a powerful inducer of IL-4 secretion, and is also known to alter host cell transcription through a nuclear localization sequence-dependent mechanism. We previously reported that IPSE ameliorates ifosfamide-induced bladder pain in an IL-4- and nuclear localization sequence-dependent manner. We hypothesized that pre-administration of IPSE to resiniferatoxin-challenged mice would dampen pain-related behaviors. IPSE indeed lessened resiniferatoxin-triggered freezing behaviors in mice. This was a nuclear localization sequence-dependent phenomenon, since administration of a nuclear localization sequence mutant version of IPSE abrogated IPSE’s analgesic effect. In contrast, IPSE’s analgesic effect did not seem IL-4-dependent, since use of anti-IL-4 antibody in mice given both IPSE and resiniferatoxin did not dramatically affect freezing behaviors. RNA-Seq analysis of resiniferatoxin- and IPSE-exposed bladders revealed differential expression of TNF/NF-κb-related signaling pathway genes. In vitro testing of IPSE uptake by urothelial cells and TRPV1-expressing neuronal cells showed uptake by both cell types. Thus, IPSE’s nuclear localization sequence-dependent therapeutic effects on TRPV1-mediated bladder pain may act on TRPV1-expressing neurons and/or may rely upon urothelial mechanisms.

scholarly journals Floral Induction in the Short-Day Plant Chrysanthemum Under Blue and Red Extended Long-Days

2021 ◽  
Vol 11 ◽  
Author(s):  
Malleshaiah SharathKumar ◽  
Ep Heuvelink ◽  
Leo F. M. Marcelis ◽  
Wim van Ieperen
Keyword(s):  
Blue Light ◽  
Floral Induction ◽  
Sole Source ◽  
Solar Light ◽  
Growth Chamber ◽  
Flower Initiation ◽  
Dependent Manner ◽  
Led Light ◽  
Short Day ◽  
Short Days

Shorter photoperiod and lower daily light integral (DLI) limit the winter greenhouse production. Extending the photoperiod by supplemental light increases biomass production but inhibits flowering in short-day plants such as Chrysanthemum morifolium. Previously, we reported that flowering in growth-chamber grown chrysanthemum with red (R) and blue (B) LED-light could also be induced in long photoperiods by applying only blue light during the last 4h of 15h long-days. This study investigates the possibility to induce flowering by extending short-days in greenhouses with 4h of blue light. Furthermore, flower induction after 4h of red light extension was tested after short-days RB-LED light in a growth-chamber and after natural solar light in a greenhouse. Plants were grown at 11h of sole source RB light (60:40) in a growth-chamber or solar light in the greenhouse (short-days). Additionally, plants were grown under long-days, which either consisted of short-days as described above extended with 4h of B or R light to long-days or of 15h continuous RB light or natural solar light. Flower initiation and normal capitulum development occurred in the blue-extended long-days in the growth-chamber after 11h of sole source RB, similarly as in short-days. However, when the blue extension was applied after 11h of full-spectrum solar light in a greenhouse, no flower initiation occurred. With red-extended long-days after 11h RB (growth-chamber) flower initiation occurred, but capitulum development was hindered. No flower initiation occurred in red-extended long-days in the greenhouse. These results indicate that multiple components of the daylight spectrum influence different phases in photoperiodic flowering in chrysanthemum in a time-dependent manner. This research shows that smart use of LED-light can open avenues for a more efficient year-round cultivation of chrysanthemum by circumventing the short-day requirement for flowering when applied in emerging vertical farm or plant factories that operate without natural solar light. In current year-round greenhouses’ production, however, extension of the natural solar light during the first 11 h of the photoperiod with either red or blue sole LED light, did inhibit flowering.

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