Hepatocyte-Derived Igκ Exerts a Protective Effect against ConA-Induced Acute Liver Injury.

Sha Yin,Xiaoyan Qiu,Yixiao Zhang,Chi Zhang,Jing Huang,Qianwen Shi,Wenwei Shao

doi:10.3390/ijms21249379

Sha Yin, Xiaoyan Qiu + Show 5 more

Open Access

https://doi.org/10.3390/ijms21249379

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Abstract

Immunoglobulin (Igκ) has been reported to be expressed in sorted liver epithelial cells of μMT mice, and the sequence characteristics of hepatocyte-derived Igκ were different from those of classical B-cell-derived Igκ. However, the physiological function of hepatocyte-derived Igκ is still unclear. The expression of Igκ was firstly identified in primary hepatocytes and normal liver cell line (NCTC1469), and hepatocyte-derived Igκ expression was elevated and displayed unique localization in hepatocytes of concanavalin A (ConA)-induced hepatitis model. Moreover, Igκ knockout mice were more sensitive to ConA-induced hepatitis and had higher serum aspartate aminotransferase (AST) levels, more severe histological injury and a greater number of terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL)-positive cells as compared with littermate controls. Furthermore, knockdown of Igκ in primary hepatocytes and NCTC1469 cells led to accelerated activation of the mitochondrial death pathway and caspase-3 cleavage in vitro, which might be related to inhibition of NF-κB signaling pathway and activation of JNK via the cytoskeleton dynamics. Taken together, these results indicate that hepatocyte-derived Igκ mediates cellular resistance to ConA-induced liver injury by inhibiting activation of caspase-3 and the mitochondrial death pathway, suggesting that Igκ plays an important role in hepatocyte survival and exerts a protective effect against ConA-induced liver injury in mice.

Highlights

According to traditional immunological theory, immunoglobulins (Igs) are generated with enormous diversity exclusively by B-lineage lymphocytes in response to various forms of antigen stimulation
To further investigate the role of hepatocyte-derived Igκ, we demonstrated that the absence of Igκ accentuated liver injury upon concanavalin A (ConA) challenge and found that Igκ is essential for hepatocyte survival
We investigated whether the Igκ gene transcript was expressed in human or mouse hepatocytes through integrative analysis of Gene Expression Omnibus (GEO) profile data

Summary

Introduction

According to traditional immunological theory, immunoglobulins (Igs) are generated with enormous diversity exclusively by B-lineage lymphocytes in response to various forms of antigen stimulation. Growing evidence indicates that non-B-cells can produce Igs (non-B-Igs) with activities distinct from antibodies Such cells include malignant tumor cells [1,2] and normal non-B-cells, including epithelial cells, skin epidermal cells, endothelial cells, neurons, germ cells, and even myeloid cells. These non-B-cells can express Igs with unique molecular characteristics, such as IgG, IgA, and IgM [3,4,5,6]. The sorted liver epithelial cells of B-cell-deficient μMT mice possess Ig heavy- and light-chain transcripts In these mice, the Ig variable region displays distinct sequence characteristics, which differ from those of the classical B-cell-derived Ig variable region [7,8]. The sequencing results from human or mouse hepatocytes in the Gene Expression Omnibus (GEO) Profile, which were provided by other research groups [9,10,11], were analyzed and revealed that these hepatocytes possess Igκtranscripts, suggesting that Igκ plays a role in the pathophysiological processes of the liver

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