Stress Proteins in Inflammatory Liver Disease

Ansgar W. Lohse and Hans Peter Dienes

Johannes Gutenberg-University, Mainz, Germany

I. INTRODUCTION

Only very few studies have thus far dealt with the expression of heat shock proteins (hsps) in normal and inflamed liver, and little is known to date on specific disease associations and immune responses to hsps in liver diseases. These studies have almost exclusively concentrated on the 60 kDa heat shock protein, hsp 60.

The liver is not only involved as a bystander organ in many systemic diseases, it is also, more than most other organs, the focus of many chronic inflammatory diseases. Hepatitis B virus infection is the most prevalent infectious disease in the world, and chronic hepatitis C appears to be similarly common worldwide, although with a different geographical distribution. Alcoholic hepatitis as the inflammatory lesion in many patients with alcoholic liver disease is thought to be largely immune mediated. Although systemic autoimmune diseases like lupus erythematosus rarely affect the liver, the liver itself is the target organ of autoimmune attack in autoimmune hepatitis (which in itself is probably a heterogeneous group of diseases), primary biliary cirrhosis, amd primary sclerosing cholangitis.

The acute phase response in systemic inflammatory conditions is centered on the liver, where protein synthesis is rapidly adjusted to the need of the endangered organism. It is likely that this massive response is associated with a marked increase in the expression of stress proteins, but data on this are not yet available.

II. HSP 60 EXPRESSION IN NORMAL LIVER

The normal liver seems to express only very low levels of hsp 60. Immuno-histology using the ML30 murine monoclonal antibody was used in two studies. In the report by Koskinas et al., very low level hsp 60 expression was found in less than 5% of hepatocytes, if at all, in healthy individuals or in those with fatty liver disease (1). These investigators did not say if staining in nonparen-chymal liver cells could be observed in the normal liver. Broome et al., using the same antibody, observed some granular cytoplasmic staining in all normal hepatocytes (2). We have studied normal liver sections using the monoclonal antibodies LK-1 and LK-2, and we also observed only minimal staining. Im-munoelectron microscopy showed that this staining was mitochondrial (3).

Using freshly isolated and cultured guinea pig hepatocytes, Kupffer cells, and sinusoidal endothelial cells, we were able to attain more information on the distribution of hsp 60 in the normal liver. Western blot analysis of solubilized proteins from these cells showed marked expression in normal hepatocytes, significant expression in Kupffer cells, and only minimal expression in normal sinusoidal endothelial cells (Fig. 1) (3). Culture of Kupffer cells at 42°C for 1 hr prior to solubilization lead to a marked increase in hsp 60 expression (Fig. 2), thus confirming the nature of it as a stress protein also in Kupffer cells. Preparation of subcellular fragments of human liver homogenate confirmed that the maximum expression was in mitochondria followed by nuclei and microsomes (3). Expression in the cytoplasm was only minimal. It thus appears that the cytoplasmic staining observed by Broome et al. (2) may either have been some nonspecific binding or, more likely, mitochondrial binding not identified as such owing to the insensitivity of light microscopy in distinguishing intracellular compartments. From our results, it can be summarized that hsp 60 is expressed in the normal liver; in particular in hepatocytes and less so in Kupffer cells. Like elsewhere in the body, it is a mitochondrial, heat stress inducible protein.

III. HSP 60 EXPRESSION IN AUTOIMMUNE LIVER DISEASES

Expression of and immunity to hsp 60, as explained elsewhere in this book, has been thought to play a critical role in the immunopathogenesis and prepetuation of autoimmune diseases. In liver disease, therefore, attention has focused on autoimmune liver disease. We have found markedly increased expression in biopsy specimens from patients with active autoimmune hepatitis (3). Very strong staining of hepatocytes and moderately strong staining of Kupffer cells was observed. In addition, sinusoidal lining cells showed some staining as well. Comparison with conventional histology showed increased expression to be

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