Downregulation of endothelin-1 by interleukin-4 during gastric ulcer healing.
We investigated the course of events associated with gastric ulcer healing by analyzing mucosal expression of interleukin-4 (IL-4), endothelin-1 (ET-1), tumor necrosis factor-alpha (TNF-alpha), and the activity of constitutive (cNOS) and inducible nitric oxide synthase (NOS-2). Ulcer onset was characterized by a massive epithelial apoptosis associated with a 5.7-fold increase in TNF-alpha, a 17.5-fold increase in NOS-2, and a 3.9-fold increase in ET-1, while mucosal expression of cNOS showed a 7.6-fold drop and IL-4 fell by 37.2%. Healing was accompanied by a rapid raise in IL-4; decrease in apoptosis, TNF-alpha, ET-1, and NOS-2; and a slow recovery in cNOS. The expression of IL-4 returned to control levels by the 7th day of healing and that of ET-1 and TNF-alpha by the 14th day, while apoptotic DNA fragmentation and the activity of NOS-2 remained significantly elevated beyond the 14-day period. The results suggest that a decrease in the mucosal level of IL-4 at ulcer onset may well be a key factor causing dysregulation of ET-1 production, induction of TNF-alpha, and triggering the apoptotic events that affect the efficiency of mucosal repair.
Slomiany
B L
BL
Research Center University of Medicine and Dentistry of New Jersey, Newark, New Jersey, 07103-2400, USA.
Piotrowski
J
J
Slomiany
A
A
D000818:Animals; D002908:Chronic Disease; D015536:Down-Regulation; D019332:Endothelin-1 / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism*; D007813:Laparotomy; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000601:surgery; D013276:Stomach Ulcer / Q000139:chemically induced / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*
D019332:Endothelin-1; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat