Murine P-glycoprotein deficiency alters intestinal injury repair and blunts lipopolysaccharide-induced radioprotection.
P-glycoprotein (P-gp) has been reported to increase stem cell proliferation and regulate apoptosis. Absence of P-gp results in decreased repair of intestinal epithelial cells after chemical injury. To further explore the mechanisms involved in the effects of P-gp on intestinal injury and repair, we used the well-characterized radiation injury model. In this model, injury repair is mediated by production of prostaglandins (PGE(2)) and lipopolysaccharide (LPS) has been shown to confer radioprotection. B6.mdr1a(-/-) mice and wild-type controls were subjected to 12 Gy total body X-ray irradiation and surviving crypts in the proximal jejunum and distal colon were evaluated 3.5 days after irradiation. B6.mdr1a(-/-) mice exhibited normal baseline stem cell proliferation and COX dependent crypt regeneration after irradiation. However, radiation induced apoptosis was increased and LPS-induced radioprotection was blunted in the C57BL6.mdr1a(-/-) distal colon, compared to B6 wild-type controls. The LPS treatment induced gene expression of the radioprotective cytokine IL-1α, in B6 wild-type controls but not in B6.mdr1a(-/-) animals. Lipopolysaccharid-induced radioprotection was absent in IL-1R1(-/-) animals, indicating a role for IL-1α in radioprotection, and demonstrating that P-gp deficiency interferes with IL-1α gene expression in response to systemic exposure to LPS.
Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294-2182, USA.
Elizabeth M
EM
Staley
Vanisha R
VR
Yarbrough
Trenton R
TR
Schoeb
Joseph G
JG
Daft
Scott M
SM
Tanner
Dennis
D
Steverson
Robin G
RG
Lorenz
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015232:Dinoprostone / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000528:radiation effects; D007113:Immunity, Innate / Q000187:drug effects / Q000528:radiation effects; D053582:Interleukin-1alpha / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000293:injuries* / Q000503:physiopathology / Q000528:radiation effects*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011833:Radiation Injuries, Experimental / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D012038:Regeneration / Q000187:drug effects / Q000528:radiation effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D053582:Interleukin-1alpha; D008070:Lipopolysaccharides; D011837:Radiation-Protective Agents; D014409:Tumor Necrosis Factor-alpha; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone