Reduced p38 mitogen-activated protein kinase in donor grafts accelerates acute intestinal graft-versus-host disease in mice.
The gastrointestinal tract is a major target of graft-versus-host disease (GVHD), which constitutes a life-threatening complication of bone marrow transplantation. GVHD is mainly caused by the activation of donor-derived lymphocytes, in which cytokine cascades play essential roles. Since p38 MAPK (p38) has been identified as a regulator of cytokine reactions and proposed as a molecular target for anti-inflammatory therapy, we investigated the contribution of p38 to the severity of murine intestinal GVHD. Unexpectedly, p38alpha(+/-) donor graft induced more acute GVHD-related mortality and more severe gut injury. The survival of p38alpha(+/-) donor-derived intestinal intraepithelial lymphocytes (IEL) was prolonged in vitro and in vivo, and TNF-alpha expression in the p38alpha(+/-) donor-derived IEL was also increased compared with wild-type cells. In contrast, the p38alpha(+/-) grafted mice resulted in decreased expansion of donor lymphocytes in mesenteric lymph nodes, and the up-regulation of IL-12p40 and IL-18 was diminished. These findings suggest that p38 has dichotomous effects for inflammatory response in vivo; not only regulates inflammatory cytokine expression and lymphocyte expansion, but also has distinct regulatory functions for IEL in intestinal GVHD. In conclusion, the inhibition of p38 may not be a suitable anti-inflammatory strategy for GVHD due to the associated intestinal injury.
Ohta
Miki
M
Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Tateishi
Keisuke
K
Kanai
Fumihiko
F
Ueha
Satoshi
S
Guleng
Bayasi
B
Washida
Miwa
M
Tanaka
Yasuo
Y
Ijichi
Hideaki
H
Ikenoue
Tsuneo
T
Sata
Masataka
M
Sudo
Tatsuhiko
T
Shiina
Shuichiro
S
Kawabe
Takao
T
Matsushima
Kouji
K
Omata
Masao
M
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016026:Bone Marrow Transplantation; D003108:Colonic Diseases / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D006086:Graft vs Host Disease / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000401:mortality; D049452:Green Fluorescent Proteins / Q000235:genetics; D016130:Immunophenotyping; D007700:Kinetics; D008214:Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048308:Mitogen-Activated Protein Kinase 14 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D012720:Severity of Illness Index
D016207:Cytokines; D049452:Green Fluorescent Proteins; D048308:Mitogen-Activated Protein Kinase 14