Anti-Inflammatory Effects of Mitogen-Activated Protein Kinase Kinase Inhibitor U0126 in an Asthma Mouse Model

Duan, Wei; Chan, Jasmine H.P.; Wong, Chui Hong; Leung, Bernard P.; Wong, W.S. Fred

doi:10.4049/jimmunol.172.11.7053

Cited by 260 publications

(216 citation statements)

References 48 publications

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“…Numerous reports have indicated a role of MAPK, particularly ERK1/2 and p38, in the regulation of COX-2 expression in monocytes [6], neuroblastoma cells [12] and epithelial cells [7], by LPS, IL-1b and TNF-a, respectively. On the other hand, an association between MAPK activity and allergic inflammation has been found previously in the lungs of asthmatic mice [9] or in the bronchoalveolar lavage fluids from asthmatic patients [8]. In agreement with these results, our work shows that the exposure of PBL from patients allergic to specific allergens promoted p38 and ERK1/2 activation.…”

Section: Discussionsupporting

confidence: 92%

“…Previous studies have pointed out a connection between this induction and the activation of MAPK-dependent pathways [6,7]. MAPK activities have also been associated with allergic inflammation [8,9]. The transcriptional activation of COX-2 is mediated by the binding of transcription factors to regulatory elements in the COX-2 promoter, such as nuclear factor of activated T cells (NF-AT) [10,11] or NF-jB [12,13].…”

Section: Introductionmentioning

confidence: 99%

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Induction of cyclooxygenase-2 expression by allergens in lymphocytes from allergic patients

et al. 2005

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Cyclooxygenase (COX) is a key enzyme in prostaglandin (PG) synthesis. Up-regulation of COX-2 expression is responsible for increased PG release during inflammatory conditions and is thought to be also involved in allergic states. In this study, we demonstrate that in human T, B and natural killer lymphocytes from allergic patients, COX-2 expression became induced upon cell challenge with specific allergens and that this process is presumably IgE dependent and occurs after CD23 receptor ligation. This induction took place at both mRNA and protein levels and was accompanied by PGD 2 release. IgE-dependent lymphocyte treatment elicited, in parallel, an activation of the MAPK p38 and extracellular signal-regulated kinase 1/2, an enhancement of calcineurin (CaN) activity, and an increase of the DNA-binding activity of the nuclear factor of activated T cells and of NF-jB, with a concomitant decrease in the levels of the cytosolic inhibitor of jB, IjB. In addition, specific chemical inhibitors of MAPK, such as PD098059 and SB203580, as well as MG-132, an inhibitor of proteasomal activity, abolished allergen-induced COX-2 up-regulation, suggesting that this process is mediated by MAPK and NF-jB. However, induction of COX-2 expression was not hampered by the CaN inhibitor cyclosporin A. We also examined the effect of a selective COX-2 inhibitor, NS-398, on cytokine production by human lymphocytes. Treatment with NS-398 severely diminished the IgE-dependently induced production of IL-8 and TNF-a. These results underscore the relevant role of lymphocyte COX-2 in allergy and suggest that COX-2 inhibitors may contribute to the improvement of allergic inflammation through the reduction of inflammatory mediator production by human lymphocytes.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Induction of cyclooxygenase-2 expression by allergens in lymphocytes from allergic patients

et al. 2005

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“…In addition to the regulation of neoplastic cell proliferation, ERK has also been implicated in the control of signaling cascades associated with eosinophilia in asthma. Duan et al (48) reported that an MEK inhibitor dramatically inhibited OVAinduced lung tissue eosinophilia and airway hyperresponsiveness. Also, p38…”

Section: Discussionmentioning

confidence: 99%

FIP1L1-PDGFRα Imposes Eosinophil Lineage Commitment on Hematopoietic Stem/Progenitor Cells

Fukushima

Matsumura

Ezoe

et al. 2009

Journal of Biological Chemistry

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Although leukemogenic tyrosine kinases (LTKs) activate a common set of downstream molecules, the phenotypes of leukemia caused by LTKs are rather distinct. Here we report the molecular mechanism underlying the development of hypereosinophilic syndrome/chronic eosinophilic leukemia by FIP1L1-PDGFR␣. When introduced into c-Kit high Sca-1 ؉ Lineage ؊ cells, FIP1L1-PDGFR␣ conferred cytokine-independent growth on these cells and enhanced their self-renewal, whereas it did not immortalize common myeloid progenitors in in vitro replating assays and transplantation assays. Importantly, FIP1L1-PDGFR␣ but not TEL-PDGFR␤ enhanced the development of Gr-1 ؉ IL-5R␣ ؉ eosinophil progenitors from c-Kit high Sca-1 ؉ Lineage ؊ cells. FIP1L1-PDGFR␣ also promoted eosinophil development from common myeloid progenitors. Furthermore, when expressed in megakaryocyte/erythrocyte progenitors and common lymphoid progenitors, FIP1L1-PDGFR␣ not only inhibited differentiation toward erythroid cells, megakaryocytes, and B-lymphocytes but aberrantly developed eosinophil progenitors from megakaryocyte/erythrocyte progenitors and common lymphoid progenitors. As for the mechanism of FIP1L1-PDGFR␣-induced eosinophil development, FIP1L1-PDGFR␣ was found to more intensely activate MEK1/2 and p38 MAPK than TEL-PDGFR␤. In addition, a MEK1/2 inhibitor and a p38 MAPK inhibitor suppressed FIP1L1-PDGFR␣-promoted eosinophil development. Also, reverse transcription-PCR analysis revealed that FIP1L1-PDGFR␣ augmented the expression of C/EBP␣, GATA-1, and GATA-2, whereas it hardly affected PU.1 expression. In addition, short hairpin RNAs against C/EBP␣ and GATA-2 and GATA-3KRR, which can act as a dominant-negative form over all GATA members, inhibited FIP1L1-PDGFR␣-induced eosinophil development. Furthermore, FIP1L1-PDGFR␣ and its downstream Ras inhibited PU.1 activity in luciferase assays. Together, these results indicate that FIP1L1-PDGFR␣ enhances eosinophil development by modifying the expression and activity of lineage-specific transcription factors through Ras/MEK and p38 MAPK cascades.

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“…To determine the extent of mucus production, goblet cell hyperplasia in the airway epithelium was quantified with a five-point grading system. 15,16) The adopted grading system was as follows: 0, no goblet cells; 1, Ͻ25%; 2, 25-50%; 3, 50-75%, and 4, Ͼ75%. The blinded quantitative analysis was performed with the described method previously.…”

Section: )mentioning

confidence: 99%

Thalidomide Attenuates Airway Hyperresponsiveness and Eosinophilic Inflammation in a Murine Model of Allergic Asthma

Asano

Kumakura

Taki

et al. 2010

Biological & Pharmaceutical Bulletin

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Bronchial asthma has clinical manifestations, which include variable degrees of airflow obstruction, airway hyperresponsiveness, and airway inflammation.1) The inflammatory process in asthma is dominated by T helper-2 (Th2) cells which produce interleukin-4 (IL-4), IL-5, and IL-13. 2)Thalidomide was synthesized in 1954 by CIBA Pharmaceutical Company, and prescribed as a sedative, tranquiliser, and antiemetic for morning sickness. Because the highest risk for teratogenicity arose when the drug was taken between weeks 3 and 8 after conception, it was withdrawn from many countries including Japan. However, the drug was revived as an effective treatment for erythema nodosum leprosum lesions in 1965. The U.S.A. Food and Drug Administration approved it for this indication in 1998. 3)Thalidomide, which is metabolized by cytochrome P450, 3,4) has a wide range of pharmaceutical and biological activities. Currently, clinical investigations of thalidomide have been conducted in patients with diverse diseases, including multiple myeloma, rheumatoid arthritis, and human immunodeficiency virus infection. 5,6) The beneficial pharmacological effects elicited by thalidomide include anti-angiogenic, anti-viral, anti-inflammatory, and immunomodulatory activities, 5,7) although the precise mechanisms are unknown.8)It has been reported that thalidomide administered with albendazole suppressed eosinophilic infiltration in cerebrospinal fluid in a murine vermination model. 9) However, little is known about the effect of thalidomide on the airway hyperresponsiveness and eosinophilic inflammation in allergic asthma.The purpose of this study was to investigate the effects of thalidomide on airway inflammation and hyperresponsiveness in a murine model of allergic asthma. We hypothesized that thalidomide would have anti-inflammatory effects in allergic asthma. MATERIALS AND METHODS Sensitisation and Challenge with OvalbuminSevenweek-old female BALB/c mice (SLC, Shizuoka) were purchased and maintained in our specific pathogen-free animal facility. The mice were maintained at room temperature (23Ϯ2°C) and humidity (55Ϯ10%) in an air-conditioned room. They were fed a standard laboratory diet and given water ad libitum. They were sensitised by an intraperitoneal injection with 100 mg ovalbumin (OVA) and 1 mg alum in 200 ml of phosphate-buffered saline (PBS) on day 0, and then by a hypodermic injection with 10 mg OVA in 20 ml of PBS on day 14. They were then placed in an acrylic chamber and challenged with 1% OVA for 10 min daily by a nebulizer (IS-2; Paris, Starnberg, Germany) between days 21 and 25. 10)Saline was used in place of OVA during the sensitisation and challenge stages of the protocol as a negative control. All protocols described in this study were approved by the Animal Ethics Committee of Nagoya University Graduate School of Medicine, Nagoya, Japan.Treatment Protocols For in vivo animal experiments, thalidomide (30, 100, or 300 mg/kg) was suspended in 0.5% carboxymethylcellulose, vortexed for 5 min, and administered orally via a ...

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Anti-Inflammatory Effects of Mitogen-Activated Protein Kinase Kinase Inhibitor U0126 in an Asthma Mouse Model

Cited by 260 publications

References 48 publications

Induction of cyclooxygenase-2 expression by allergens in lymphocytes from allergic patients

Induction of cyclooxygenase-2 expression by allergens in lymphocytes from allergic patients

FIP1L1-PDGFRα Imposes Eosinophil Lineage Commitment on Hematopoietic Stem/Progenitor Cells

Thalidomide Attenuates Airway Hyperresponsiveness and Eosinophilic Inflammation in a Murine Model of Allergic Asthma

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