Specific Role of Interleukin-1 in Hepatic Neutrophil Recruitment after Ischemia/Reperfusion

Abstract

Hepatic ischemia/reperfusion injury is caused primarily by the products of neutrophils recruited into the liver after reperfusion. The mediators responsible for the development of this inflammatory response are thought to be tumor necrosis factor-alpha and interleukin (IL)-1. Although there is abundant evidence to support a role for tumor necrosis factor-alpha, much less is known about the function of IL-1 in this injury. In the present studies, we investigated whether IL-1 was a critical mediator for the induction of liver inflammation after ischemia/reperfusion. Wild-type and IL-1 receptor I-knockout (IL-1RI(-/-)) mice were exposed to 90 minutes of partial hepatic ischemia and up to 24 hours of reperfusion. In wild-type mice, IL-1beta expression was maximal after ischemia and 8 hours of reperfusion. At the same time, both wild-type and IL-1RI(-/-) mice had severe liver injury as assessed by serum alanine aminotransferase levels and hepatic histopathology. However, IL-1RI(-/-) mice had significantly less neutrophil accumulation in liver tissues as measured by liver myeloperoxidase content and histology. The reduction in hepatic neutrophil recruitment in IL-1RI(-/-) mice was associated with decreased activation of the transcription factor, nuclear factor-kappaB, and reduced expression of the CXC chemokine, macrophage inflammatory protein-2. These data suggest that IL-1 functions to augment neutrophil accumulation, but does not play an essential role in this response.

SP600125, a selective JNK inhibitor, aggravates hepatic ischemia-reperfusion injury

“…Male C57BL/6 mice weighing 25 to 30 g (Orient, Korea) were allowed free access to food and water before and after hepatic I/R. Six mice in each group were subjected to partial hepatic I/R procedures, as described previously (Kato et al, 2002) with slight modification. In brief, mice were anesthetized by enflurane inhalation using a nose cone.…”

“…JNK is activated by environmental stresses such as oxidative stress (Mendelson et al, 1996), and also by cytokines, including TNF- (Liedtke et al, 2002) and IL-1 (Finch et al, 2001). These cytokines are considered to be major mediators in hepatic I/R injury (Kato et al, 2002;Teoh et al, 2004). JNK activation during reperfusion is believed to play a role in hepatocyte apoptosis (Marderstein et al, 2003;Uehara et al, 2004;Uehara et al, 2005).…”

Distinct contributions of CD4+T cell subsets in hepatic ischemia/reperfusion injury

“…Activated Kupffer cells also induce activation of redox-sensitive transcription factors such as NF-B, which results in release of many proinflammatory mediators (28,42). Proximal cytokines, such as IL-12, TNF-␣, and IL-1, are critically involved in promoting the second phase of liver injury by inducing the hepatic expression of neutrophil-attracting CXC chemokines and endothelial cell adhesion molecules (6,19,29). The cooperative effects of CXC chemokines and adhesion molecules result in adherence of neutrophils in the hepatic microcirculation and their subsequent transmigration into the hepatic parenchyma (18).…”

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“…Kato and associates were the first to provide important information regarding the role of IL-1 in the inflammatory injury induced by hepatic IRI. 32 Their data indicated that IL-1 functions to induce nuclear factor-κB activation and expression of CXC chemokines during the later phases of this inflammatory response. These effects augmented the recruitment of neutrophils to the hepatic parenchyma but did not significantly alter the extent of hepatocellular injury.…”