A Functional Analysis of EP4 Receptor-Expressing Neurons in Mediating the Action of Prostaglandin E2 Within Specific Nuclei of the Brain in Response to Circulating Interleukin-1β

Prostaglandin E2 (PGE2) is a key mediator of inflammation, and consequently huge efforts have been devoted to the development of novel agents able to regulate its formation. In this work, we present the synthesis of various α-ketoheterocycles and a study of their ability to inhibit the formation of PGE2 at a cellular level. A series of α-ketobenzothiazoles, α-ketobenzoxazoles, α-ketobenzimidazoles, and α-keto-1,2,4-oxadiazoles were synthesized and chemically characterized. Evaluation of their ability to suppress the generation of PGE2 in interleukin-1β plus forskolin-stimulated mesangial cells led to the identification of one α-ketobenzothiazole (GK181) and one α-ketobenzoxazole (GK491), which are able to suppress the PGE2 generation at a nanomolar level.

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A Nonprostanoid EP4 Receptor Selective Prostaglandin E2 Agonist Restores Bone Mass and Strength in Aged, Ovariectomized Rats

Journal of Bone and Mineral Research ◽

10.1359/jbmr.051110 ◽

2005 ◽

Vol 21 (4) ◽

pp. 565-575 ◽

Cited By ~ 39

Author(s):

Hua Zhu Ke ◽

D Todd Crawford ◽

Hong Qi ◽

Hollis A Simmons ◽

Thomas A Owen ◽

...

Keyword(s):

Bone Mass ◽

Prostaglandin E2 ◽

Ovariectomized Rats ◽

Ep4 Receptor

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Direct Melanoma Cell Contact Induces Stromal Cell Autocrine Prostaglandin E2-EP4 Receptor Signaling That Drives Tumor Growth, Angiogenesis, and Metastasis

Journal of Biological Chemistry ◽

10.1074/jbc.m115.669481 ◽

2015 ◽

Vol 290 (50) ◽

pp. 29781-29793 ◽

Cited By ~ 21

Author(s):

Masaki Inada ◽

Morichika Takita ◽

Satoshi Yokoyama ◽

Kenta Watanabe ◽

Tsukasa Tominari ◽

...

Keyword(s):

Tumor Growth ◽

Prostaglandin E2 ◽

Melanoma Cell ◽

Stromal Cell ◽

Cell Contact ◽

Receptor Signaling ◽

Ep4 Receptor

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Cholecystokinin Inhibits Food Intake Independent of Interleukin-1β Expression in the Brain

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.26.1181 ◽

2003 ◽

Vol 26 (8) ◽

pp. 1181-1183 ◽

Cited By ~ 3

Author(s):

Libin Zhan ◽

Toru Hosoi ◽

Yasunobu Okuma ◽

Yasuyuki Nomura

Keyword(s):

Food Intake ◽

Interleukin 1Β ◽

The Brain

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The contribution of the vagus nerve in interleukin-1β-induced fever is dependent on dose

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.280.4.r929 ◽

2001 ◽

Vol 280 (4) ◽

pp. R929-R934 ◽

Cited By ~ 86

Author(s):

Michael K. Hansen ◽

Kevin A. O'Connor ◽

Lisa E. Goehler ◽

Linda R. Watkins ◽

Steven F. Maier

Keyword(s):

Core Body Temperature ◽

Vagal Afferents ◽

Interleukin 1Β ◽

Blood Levels ◽

Low Doses ◽

Neural Pathway ◽

Subdiaphragmatic Vagotomy ◽

Core Body ◽

Neural Signaling ◽

The Brain

It has been suggested that proinflammatory cytokines communicate to the brain via a neural pathway involving activation of vagal afferents by interleukin-1β (IL-1β), in addition to blood-borne routes. In support, subdiaphragmatic vagotomy blocks IL-1β-induced, brain-mediated responses such as fever. However, vagotomy has also been reported to be ineffective. Neural signaling would be expected to be especially important at low doses of cytokine, when local actions could occur, but only very small quantities of cytokine would become systemic. Here, we examined core body temperature after intraperitoneal injections of three doses of recombinat human IL-1β (rh-IL-1β). Subdiaphragmatic vagotomy completely blocked the fever produced by 0.1 μg/kg, only partially blocked the fever produced by 0.5 μg/kg, and had no effect at all on the fever that followed 1.0 μg/kg rh-IL-1β. Blood levels of rh-IL-1β did not become greater than normal basal levels of endogenous rat IL-β until the 0.5-μg/kg dose nor was IL-1β induced in the pituitary until this dose. These results suggest that low doses of intraperitoneal IL-1β induce fever via a vagal route and that dose may account for some of the discrepancies in the literature.

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