title: Toll-like receptor 4 protects against stress-induced ulcers via regulation of glucocorticoid production in mice.
abstract: Stress-induced gastric ulcer is an important life-threatening condition, while the molecular basis of its development is incompletely understood. Toll-like receptor 4 (TLR4), an innate immune pattern recognition receptor, can induce pro-inflammatory transcription, aggravating a stress ulcer. The present study found that TLR4 played a protective role in a mouse model of water immersion (23 °C) restraint stress. Wild-type (WT) and TLR4-/-male mice were respectively divided into five groups (5 per group), and exposed to the stressor for 0, 0.5, 1, 2, or 4 hours. Gastric ulcer index, determined post mortem, increased with time in both types of mice but was greater in TLR4-/-mice. Furthermore, increased serum cortisol and corticosterone concentrations were observed in WT mice only, and such increases were detected only in WT mice 4 h after lipopolysaccharide (LPS) treatment (2 mg/kg, intraperitoneal injection). Moreover, the administration of cortisol alleviated the gastric injury in TLR4-/-mice. Western blotting showed expression in the adrenal of P450scc (CYP11A1), the first rate-limiting enzyme in the synthesis of steroids, was increased 4 h after water immersion restraint stress or LPS treatment in WT mice, but was conversely decreased in TLR4-/-mice after either stressor. Furthermore, in adrenal glands of TLR4-/-mice, structural distortion of mitochondria (which contain CYP11A1) was found with electron microscopy, and lack of lipid-storing droplets was found using light microscopy on adrenal cryosections stained with Oil red O. These data indicate that TLR4 plays a protective role in stress-induced gastric ulcer that is exerted via impacting synthesis of glucocorticoid in the adrenal gland.
authors.affiliation: a Department of Burn Surgery , Changhai Hospital, The Second Military Medical University , Shanghai , China.
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.affiliation: a Department of Burn Surgery , Changhai Hospital, The Second Military Medical University , Shanghai , China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Luo
authors.affiliation: a Department of Burn Surgery , Changhai Hospital, The Second Military Medical University , Shanghai , China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhang
authors.affiliation: b Department of Ophthalmology , Renji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China.
authors.forename: Yuelu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: a Department of Burn Surgery , Changhai Hospital, The Second Military Medical University , Shanghai , China.
authors.forename: Xingtong
authors.initials: X
authors.lastname: Wang
authors.affiliation: c Department of Burn and Plastic Surgery , Zhangjiagang First People's Hospital , Suzhou , China.
authors.forename: Fei
authors.initials: F
authors.lastname: Chang
authors.affiliation: d Department of Pharmacy , Zhangjiagang Hospital of Traditional Chinese Medicine, Nanjing University of Chinese Medicine , Suzhou , China.
authors.forename: Yuechan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: a Department of Burn Surgery , Changhai Hospital, The Second Military Medical University , Shanghai , China.
authors.forename: Hongtai
authors.initials: H
authors.lastname: Tang
authors.affiliation: a Department of Burn Surgery , Changhai Hospital, The Second Military Medical University , Shanghai , China.
authors.forename: Zhaofan
authors.initials: Z
authors.lastname: Xia
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D005938:Glucocorticoids; D006854:Hydrocortisone / Q000097:blood; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012149:Restraint, Physical; D015398:Signal Transduction / Q000187:drug effects; D013276:Stomach Ulcer / Q000209:etiology / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; D003345:Corticosterone; D006854:Hydrocortisone
keywords: Cortisol; LPS; TLR4; glucocorticoid; stomach ulcer; stress