Effect of Protease-Activated Receptor-2 Deficiency on Allergic Dermatitis in the Mouse Ear

Kawagoe, J.; Takizawa, Tomoko; Matsumoto, Jiro; Tamiya, Masaki; Meek, Stephen; Smith, Andrew J.H.; Hunter, Gary D.; Plevin, Robin; Saito, Naohiro; Kanke, Toru; Fujii, Masaaki; Wada, Yasushi

doi:10.1254/jjp.88.77

Cited by 89 publications

(62 citation statements)

References 43 publications

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“…These studies, combined with the early observation of increased PAR-2 mRNA expression following cytokine pre-treatment of vascular endothelial cells (21), strongly suggested a role for PAR-2 in the integration of vascular inflammation. Similar mechanisms may be responsible in our observation on contact-induced skin inflammation, which was abrogated in PAR-2-gene-deficient mice (22). Another line of evidence for PAR-2 in association with chronic inflammation was demonstrated in an adjuvant monoarthritis model (23).…”

Section: Physiological Studies Using Par-2-gene-deficient Micesupporting

confidence: 88%

Physiology and Pathophysiology of Proteinase-Activated Receptors (PARs): PAR-2 as a Potential Therapeutic Target

et al. 2005

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Abstract. PAR-2 is the second member of the family of proteinase-activated receptors activated by trypsin, tryptase, and several other serine proteinases. In order to evaluate the therapeutic potential for PAR-2, we have performed studies on PAR-2-mediated signal transduction and investigated the effects of PAR-2 gene deficiency in disease models. In addition to the Gprotein-coupled receptor-mediated common signal transduction pathways, inositol 1,4,5-trisphosphate production and mobilization of Ca

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Section: Physiological Studies Using Par-2-gene-deficient Micesupporting

confidence: 88%

Physiology and Pathophysiology of Proteinase-Activated Receptors (PARs): PAR-2 as a Potential Therapeutic Target

et al. 2005

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“…The inability of OVX to increase the CHS response may be due to maximization of ear thickness, since the maximal change possible appears to be about 0 . 11 mm (Kawagoe et al 2002) and ear thickness observed in our study was about 0 . 1 mm, and thus was already at the top of the range.…”

Section: Resultssupporting

confidence: 50%

Local cytokine levels associated with delayed-type hypersensitivity responses: modulation by gender, ovariectomy, and estrogen replacement

Lisa

Guzmán

Muller

et al. 2007

Journal of Endocrinology

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It is well established that females mount stronger immune responses than males, but only very little is understood about the underlying mechanisms. We have analyzed local cytokine differences among intact females, those that had been ovariectomized (OVX), those receiving estrogen replacement after OVX, and males, both before and after production of delayed-type hypersensitivity (DTH) responses. We report confirmation of a much larger DTH response in females versus males. However, OVX resulted in an even larger response, while estrogen replacement resulted in a smaller response when compared with intact females. In animals exposed for the first time to an antigen (without a DTH response), OVX increased interleukin-6 (IL-6) and estrogen replacement after OVX suppressed IL-6. Of the cytokines that differed between males and females exposed for the first time to an antigen, only IL-6 was higher in females versus males when exposure to antigen occurred for the second time (when the DTH response occurs). Analysis of cytokines with OVX and estrogen replacement after a second exposure to antigen showed that IL-6 did not significantly change. Levels of IL-4; Regulated upon Activation, Normal T-cell Expressed; and Secreted; and thrombopoietin, however, correlated with the DTH response, suggesting direct or indirect positive regulation by estrogen. These results suggest an important role for both IL-6 and IL-4 in determining the degree of DTH response, with IL-6 (which appears negatively regulated by estrogen) increasing and IL-4 (which appears positively regulated by estrogen) decreasing the response. The results further suggest that IL-6 may play a role in predisposing to a larger DTH response, while IL-4 levels seem more important during an active response.

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“…Particularly, in the respiratory system, PAR2 is abundantly expressed in the epithelial cells, and its activation by the endogenous and exogenous proteinases leads to release of pro-inflammatory mediators including cyto-kines and prostanoids (10 -12). It is also to be noted that the pro-inflammatory role of PAR2 has been well described in the gastrointestinal tract (13), kidney (14), skin (15), synovial joints (16), and so on.…”

Section: Introductionmentioning

confidence: 99%

Proteinase-Activated Receptor-2–Triggered Prostaglandin E2 Release, but Not Cyclooxygenase-2 Upregulation, Requires Activation of the Phosphatidylinositol 3–Kinase / Akt / Nuclear Factor-κB Pathway in Human Alveolar Epithelial Cells

et al. 2009

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Abstract. Proteinase-activated receptor-2 (PAR2) triggers upregulation of cyclooxygenase-2 (COX-2) and prostaglandin E 2 (PGE 2 ) formation in human alveolar epithelial A549 cells. This COX-2 upregulation appears to involve the Src / epidermal growth factor (EGF) receptor / p38 MAP kinase (p38MAPK) pathway and also the cAMP-response element-binding protein (CREB) pathway. Here, we investigated the roles of nuclear factor-κB (NF-κB)-related signals in the PAR2-triggered PGE 2 release / COX-2 upregulation in A549 cells. The PAR2-triggered PGE 2 release was clearly blocked by an inhibitor of the NF-κB pathway. Stimulation of PAR2 actually caused phosphorylation of inhibitor-κB, an indicator of NF-κB activation, an effect being blocked by inhibitors of MEK, phosphatidylinositol 3-kinase (PI3-kinase), and Akt, but little or not by inhibitors of p38MAPK and JNK. Stimulation of PAR2 also caused phosphorylation of Akt, an effect suppressed by inhibitors of PI3-kinase and MEK. Nonetheless, the PAR2-triggered upregulation of COX-2 was resistant to inhibitors of NF-κB, PI3-kinase, and Akt, but was attenuated by inhibitors of MEK and JNK. Stimulation of PAR2 induced phosphorylation of CREB, an effect abolished by an inhibitor of MEK but not inhibitors of p38MAPK and EGF receptor. These findings demonstrate that the MEK / ERK / PI3-kinase / Akt / NF-κB pathway is involved in PAR2-triggered PGE 2 formation, but not upregulation of COX-2 that is dependent on activation of ERK /CREB and JNK in addition to p38MAPK.

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Effect of Protease-Activated Receptor-2 Deficiency on Allergic Dermatitis in the Mouse Ear

Cited by 89 publications

References 43 publications

Physiology and Pathophysiology of Proteinase-Activated Receptors (PARs): PAR-2 as a Potential Therapeutic Target

Physiology and Pathophysiology of Proteinase-Activated Receptors (PARs): PAR-2 as a Potential Therapeutic Target

Local cytokine levels associated with delayed-type hypersensitivity responses: modulation by gender, ovariectomy, and estrogen replacement

Proteinase-Activated Receptor-2–Triggered Prostaglandin E2 Release, but Not Cyclooxygenase-2 Upregulation, Requires Activation of the Phosphatidylinositol 3–Kinase / Akt / Nuclear Factor-κB Pathway in Human Alveolar Epithelial Cells

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