Introduction

The liver is an indispensable organ that performs essential metabolic functions including the synthesis, storage and redistribution of carbohydrates, amino acids and fat and also has a major role in the detoxification and excretion of many ingested toxins. The role of the liver in innate and adaptive immunity has received little attention for a long time. Evidence is accumulating that the liver has very specific immunologic properties and that it contains a large number of resident and non-resident cells that participate in the regulation of inflammatory and immune responses [1]. Due to its anatomical links to the gut through the portal vein, which carries nutrient-rich blood from the intestine to the liver, the liver is the major target of gut-derived bacteria and bacterial products and acts as a first line of defense. The liver functions as a major filter organ for bacterial products. For example, up to 80% of intravenously injected endotoxin is detected in the liver within 20-30 min [2, 3]. Kupffer cells, the resident macrophages of the liver, are able to efficiently take up endotoxin and phagocytose bacteria carried through portal vein blood and are considered to play a major role in the clearance of systemic bacterial infection [4-6]. Despite the constant exposure to low levels of gut-derived bacteria and bacterial products, there are no signs of ongoing inflammation in the healthy liver. This lack of response is to some extent explained by the high degree of tolerance that is found in the liver. Liver tolerance is typified by graft survival across major histocompati-bility antigen disparities, induction of systemic tolerance to food antigens and persistence of some viral infections for decades [7]. Continuous exposure to low levels of lipopolysaccharides (LPS) may induce LPS tolerance [8] through several mechanisms including the LPS-induced downregulation of TLR4, the major receptor for LPS [9]. Indeed, TLR4 expression in the liver differs from other organs in that TLR4 levels are low in the liver and cannot be further induced by proinflammatory mediators such as IL-1P and TNF-a [10]. Furthermore, hepatic dendritic cells and Kupf-fer cells show a much lower expression of TLR4 and CD14, respectively, than elsewhere in the body which may also contribute to the hepatic tolerance towards LPS [11, 12]. It has also been shown that the healthy liver contains low mRNA levels of

Toll-like Receptors in Inflammation, edited by Luke A.J. O'Neill and Elizabeth Brint © 2006 Birkhäuser Verlag Basel/Switzerland

Table 1 - Toll-like receptor expression in hepatic cell populations

Cell

Main functions

TLR

TLR signals

population

expression

Hepatocyte

Albumin synthesis,

TLR2,3,4

TLR2: Modest increase in NF-kB

metabolic (protein, fat,

activation and SAA production

carbohydrate),

TLR3: Upregulation of IFN-

detoxification

responsive genes

TLR4: Modest increase in NF-

kB activation and SAA production

Hepatic

Retinoid storage,

TLR4

TLR4: NF-kB and JNK activation,

stellate cell

fibrogenesis

chemokine secretion, effects on

fibrogenesis unknown

Biliary epi

Lining of bile ducts

TLR2,3,4,5

TLR4: NF-kB activation and

thelial cell

TNF-a secretion

Sinusoidal

Lining of sinusoids,

Not known

Not known

endothelial

filtration of sinusoidal

cell

blood

Kupffer cell

Phagocytosis, antigen

TLR2,(3)*,4,(9)*

TLR2,3*,4*: NF-kB activation

presentation, cytokine

and increased TNF-a, IL-1P, IL-6,

secretion

IL-12 and IL-18 secretion

TLR9*: Increased TNF-a, IL-6 and

IL-12 secretion

Dendritic

Professional antigen

TLR4,(9)

TLR4: Increased TNF-a ,IL-1P,

cell

presentation

IL-6, IL-12 and IL-18 secretion

cytokine secretion

TLR9: Increased TNF-a ,IFN-a,

IL-6, IL-12

* unpublished data. Brackets indicate TLR expression as suggested by functional assays.

* unpublished data. Brackets indicate TLR expression as suggested by functional assays.

TLR1,2,4,6,7,8,9,10, MD-2 and MyD88 in comparison to other organs [13]. Additionally, it is likely that a decrease in IRAK and Gi-protein expression as well as an increase in SOCS-1, IRAK-M and IkB levels also contribute to this tolerance. Under conditions like alcoholism, liver cirrhosis, ischemia-reperfusion and partial hepate-ctomy, the levels of portal blood endotoxin are significantly increased [14, 15]. Endotoxin is a key player in the pathophysiology of these diseases and initiates signaling cascades that trigger proinflammatory, pro-apoptotic and proliferative responses in the liver. Liver injury induced by carbon tetrachloride, choline-deficient diet or alcohol is mitigated by nonabsorbable oral antibiotics, colectomy or germfree conditions suggesting a prominent role for LPS in the pathophysiology of these diseases [16-18]. Conversely, it has been shown that the injection of LPS augments liver injury by alcohol or choline-deficient diet [19-21]. The hepatic response to LPS is mediated by several hepatic cell populations that express TLRs and are part of a cellular network involved in the hepatic wound healing and regenerative response. In this chapter, we will describe the role of TLRs in hepatocytes, biliary epithelial cells, hepatic stellate cells, Kupffer cells and hepatic dendritic cells and highlight the importance of TLR receptors in the pathophysiology of several disease states including alcoholic liver disease, hepatic regeneration, hepatic ischemia reperfusion injury, hepatic infection and hepatic fibrosis.

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