Interleukin-1-dependent sequential chemokine expression and inflammatory cell infiltration in ischemia-reperfusion injury.
OBJECTIVE
Ischemia-reperfusion injury is known to cause organ failure, but the mechanisms of pathogenesis remain unclear. Inflammation is a factor in tissue destruction in ischemia reperfusion injury, and interleukin (IL)-1 is a key promoter of inflammation.


METHODS
Prospective, randomized, and controlled study.


METHODS
University laboratory.


METHODS
Male mice 6-8 wks of age, in which genes for IL-1alpha and IL-1beta (IL-1alpha/beta deficient) and IL-1 receptor antagonist (IL-1RA deficient) are deleted by homologous recombination, and wild-type controls on a Balb/c background.


METHODS
In this study, the role of IL-1 on inflammatory cascades, including chemokine expression, inflammatory cell infiltration, and tissue destruction, was investigated in 45 mins of unilateral renal ischemic injury using IL-1alpha/beta-deficient mice and IL-1RA-deficient mice. In addition, the effects of IL-1 on chemokine expression in cultured tubular epithelial cells were investigated.


RESULTS
In vivo study revealed that the number of interstitial infiltrated neutrophils and macrophages, which accompanied the increase of the serum levels of keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-1alpha, respectively, significantly increased in IL-1RA-deficient mice. The number of interstitial infiltrated neutrophils correlated well with serum levels of KC at 24 hrs after reperfusion, whereas the number of interstitial infiltrated macrophages correlated well with the serum levels of MIP-1alpha and monocyte chemoattractant protein (MCP)-1 at 24 and 48 hrs after reperfusion, respectively. Likewise, in vitro study revealed that stimulation of tubular epithelial cells by IL-1beta and/or H2O2 sequentially induced KC, MIP-1alpha, and MCP-1 in both protein and messenger RNA levels, which is consistent with in vivo results.


CONCLUSIONS
IL-1-dependent inflammatory cascades, followed by inflammatory cell infiltration and subsequent tissue destruction, may affect pathogenesis of renal ischemia-reperfusion injury.
Furuichi
Kengo
K
Department of Gastroenterology and Nephrology and Division of Blood Purification, Kanazawa University, Japan.
Wada
Takashi
T
Iwata
Yasunori
Y
Kokubo
Satoshi
S
Hara
Akinori
A
Yamahana
Junya
J
Sugaya
Takeshi
T
Iwakura
Yoichiro
Y
Matsushima
Kouji
K
Asano
Masahide
M
Yokoyama
Hitoshi
H
Kaneko
Shuichi
S
D000818:Animals; D018932:Chemokine CCL2 / Q000097:blood*; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines / Q000097:blood*; D020287:In Situ Nick-End Labeling; D007375:Interleukin-1 / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007683:Kidney Tubular Necrosis, Acute / Q000378:metabolism / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000097:blood*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000378:metabolism; D011446:Prospective Studies; D011897:Random Allocation; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology
D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines; D007375:Interleukin-1; D019402:Macrophage Inflammatory Proteins