| Budget Amount *help |
¥3,970,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥570,000)
Fiscal Year 2007: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
There have been new developments in biological functions of the inter-alpha inhibitor (IaI) family. The anti-proteolytic activity of IaI family originates from bikunin (also known as urinary trypsin inhibitor). There is growing evidence that bikunin is not just an anti-proteolytic agent but is considered to be an anti-inflammatory agent which suppresses the lipopolysaccharide (LPS) -induced cytokine synthesis. Bikunin functions to inhibit calcium influx and extracellular signal-regulated kinase (ERE) signaling via LPS receptors and/or as yet unidentified bikunin signaling receptors. Through LPS signaling receptor, LPS increases calcium influx and phosphorylates ERK, which activates multiple transcription factors, nuclear factor kappaB (NFκB) or early growth response-1 (Egr-1), all leading to promote cytokine expression. Deficits in signaling cascades by free bikunin or cell-bound bikunin are predicted to down-regulate cytokine expression, render macrophages/neutrophils more inactivatio
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n, and impair inflammatory process. This review largely focuses on our current understanding of the apparent functions of bikunin, its ligands, the effector molecules with which it interacts, and its regulation.
Based on several working models, specific roles of bikunin, including KTI, have been proposed: 1) LPS increases the binding capacity of the macrophages for bikunin and its incorporation into them; 2) bikunin first directly interacts with bacterial toxins including LPS, which enhances trapping of bacterial toxins; 3) bikunin causes a decrease in the binding of LPS to macrophages; 4) bikunin interacts with activated inflammatory cell surface via CD44-bound Link protein and/or unknown components as well as inactivates some membrane-bound proteinases; 5) bikunin inhibits the LPS-induced increase in calcium influx, which triggers a signal that inactivates mitogen-activated protein kinase kinase (MAPKK [MEK]) /ERK1/2 and NFkB, leading to suppression of LPS-induced cytokine synthesis; 6)ERK1/2 also phosphorylates specific nuclear transcription factors. However, there is a conflicting data in which bikunin does not inhibit the activation of NFkB, although it inhibited ERK1/2 activation-dependent Egr-1 expression in monocytes stimulated with LPS; and finally, 7) the protective role of bikunin against acute inflammatory organ injury induced by LPS was confirmed using bikunin-deficient (Knockout) mice and corresponding wild-type mice, suggesting that endogenous bikunin is protective against acute organ injury or inflammatory reaction induced by LPS. Thus, a growing body of evidence has accumulated that bikunin impairs LPS-induced inflammatory genes and cytokine expression that promote organ injury. Bikunin does inhibit LPS-induced ERK1/2 activation by suppressing an increase in calcium influx, leading to suppression of ERK1/2-induced activation of transcription factors, including Egr-1. All effects could be explained by which bikunin directly interacts with LPS, inactivates the LPS receptor system, or blocks calcium influx. Therefore, bikunin is not just an anti proteolytic agent but is considered to be an anti-inflammatory agent which suppresses the LPS-induced cytokine synthesis. Less
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