Lipopolysaccharide downregulates macrophage-derived IL-22 to modulate alcohol-induced hepatocyte cell death

Yaming Liu, Vikas K. Verma, Harmeet Malhi, Greg J. Gores, Patrick S. Kamath, Arun Sanyal, Naga Chalasani, Bin Gao, Vijay H. Shah

Research output: Contribution to journalArticle

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Abstract

Interleukin-22 (IL-22) is a Th17 cell hepatoprotective cytokine that is undergoing clinical trials to treat patients with alcoholic hepatitis (AH). Lipopolysaccharide (LPS) activation of macrophage is implicated in hepatocyte cell death and pathogenesis of AH. The role of IL-22 production from macrophage, its regulation by LPS, and effects on alcohol-induced hepatocyte cell death are unexplored and were examined in this study. Low levels of IL-22 mRNA/protein were detected in macrophage but were significantly upregulated by 6.5-fold in response to the tissue reparative cytokine IL-10. Conversely, LPS significantly decreased IL-22 mRNA levels in a temporal and concentration- dependent manner with a maximum reduction of 5-fold. LPS downregulation of IL-22 mRNA levels was rescued in the presence of a pharmacological inhibitor of c-Jun NH2-terminal kinase (JNK) and by JNK knockdown. Next, we explored whether macrophage- derived IL-22 regulated ethanol-induced hepatocyte death. Conditioned media from IL-10-stimulated macrophages attenuated ethanol-induced hepatocyte caspase-3/7 activity, and apoptosis as assessed by fluorometric assay and TdT-mediated dUTP nick-end labeling (TUNEL) staining, respectively. This effect was diminished in conditioned media from macrophages with IL-22 knockdown. Cytokine analysis in sera samples of patients with AH revealed that IL-22 levels were significantly elevated compared with healthy controls and heavy-drinking controls, implying a state of IL-22 resistance in human AH. Macrophage-derived IL-22 protects hepatocytes from ethanol-induced cell death. IL-22 downregulation is a new regulatory target of LPS in the pathogenesis of AH.

Original languageEnglish (US)
Pages (from-to)C305-C313
JournalAmerican Journal of Physiology - Cell Physiology
Volume313
Issue number3
DOIs
StatePublished - Sep 5 2017

Fingerprint

Lipopolysaccharides
Hepatocytes
Cell Death
Down-Regulation
Macrophages
Alcohols
Alcoholic Hepatitis
Ethanol
JNK Mitogen-Activated Protein Kinases
Conditioned Culture Medium
Cytokines
Interleukin-10
Messenger RNA
interleukin-22
Caspase 7
Th17 Cells
Macrophage Activation
Caspase 3
Drinking
Clinical Trials

Keywords

  • AH
  • Alcohol
  • Alcoholic hepatitis
  • Apoptosis
  • ASH
  • Caspase
  • Ethanol
  • Hepatotoxicity
  • Immune cells
  • Inflammation
  • Interleukin-22
  • JNK
  • Liver
  • Macrophage
  • MAPK
  • SP600125
  • Th17
  • TUNEL
  • U0126

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

Cite this

Lipopolysaccharide downregulates macrophage-derived IL-22 to modulate alcohol-induced hepatocyte cell death. / Liu, Yaming; Verma, Vikas K.; Malhi, Harmeet; Gores, Greg J.; Kamath, Patrick S.; Sanyal, Arun; Chalasani, Naga; Gao, Bin; Shah, Vijay H.

In: American Journal of Physiology - Cell Physiology, Vol. 313, No. 3, 05.09.2017, p. C305-C313.

Research output: Contribution to journalArticle

Liu, Yaming ; Verma, Vikas K. ; Malhi, Harmeet ; Gores, Greg J. ; Kamath, Patrick S. ; Sanyal, Arun ; Chalasani, Naga ; Gao, Bin ; Shah, Vijay H. / Lipopolysaccharide downregulates macrophage-derived IL-22 to modulate alcohol-induced hepatocyte cell death. In: American Journal of Physiology - Cell Physiology. 2017 ; Vol. 313, No. 3. pp. C305-C313.
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abstract = "Interleukin-22 (IL-22) is a Th17 cell hepatoprotective cytokine that is undergoing clinical trials to treat patients with alcoholic hepatitis (AH). Lipopolysaccharide (LPS) activation of macrophage is implicated in hepatocyte cell death and pathogenesis of AH. The role of IL-22 production from macrophage, its regulation by LPS, and effects on alcohol-induced hepatocyte cell death are unexplored and were examined in this study. Low levels of IL-22 mRNA/protein were detected in macrophage but were significantly upregulated by 6.5-fold in response to the tissue reparative cytokine IL-10. Conversely, LPS significantly decreased IL-22 mRNA levels in a temporal and concentration- dependent manner with a maximum reduction of 5-fold. LPS downregulation of IL-22 mRNA levels was rescued in the presence of a pharmacological inhibitor of c-Jun NH2-terminal kinase (JNK) and by JNK knockdown. Next, we explored whether macrophage- derived IL-22 regulated ethanol-induced hepatocyte death. Conditioned media from IL-10-stimulated macrophages attenuated ethanol-induced hepatocyte caspase-3/7 activity, and apoptosis as assessed by fluorometric assay and TdT-mediated dUTP nick-end labeling (TUNEL) staining, respectively. This effect was diminished in conditioned media from macrophages with IL-22 knockdown. Cytokine analysis in sera samples of patients with AH revealed that IL-22 levels were significantly elevated compared with healthy controls and heavy-drinking controls, implying a state of IL-22 resistance in human AH. Macrophage-derived IL-22 protects hepatocytes from ethanol-induced cell death. IL-22 downregulation is a new regulatory target of LPS in the pathogenesis of AH.",
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AU - Liu, Yaming

AU - Verma, Vikas K.

AU - Malhi, Harmeet

AU - Gores, Greg J.

AU - Kamath, Patrick S.

AU - Sanyal, Arun

AU - Chalasani, Naga

AU - Gao, Bin

AU - Shah, Vijay H.

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AB - Interleukin-22 (IL-22) is a Th17 cell hepatoprotective cytokine that is undergoing clinical trials to treat patients with alcoholic hepatitis (AH). Lipopolysaccharide (LPS) activation of macrophage is implicated in hepatocyte cell death and pathogenesis of AH. The role of IL-22 production from macrophage, its regulation by LPS, and effects on alcohol-induced hepatocyte cell death are unexplored and were examined in this study. Low levels of IL-22 mRNA/protein were detected in macrophage but were significantly upregulated by 6.5-fold in response to the tissue reparative cytokine IL-10. Conversely, LPS significantly decreased IL-22 mRNA levels in a temporal and concentration- dependent manner with a maximum reduction of 5-fold. LPS downregulation of IL-22 mRNA levels was rescued in the presence of a pharmacological inhibitor of c-Jun NH2-terminal kinase (JNK) and by JNK knockdown. Next, we explored whether macrophage- derived IL-22 regulated ethanol-induced hepatocyte death. Conditioned media from IL-10-stimulated macrophages attenuated ethanol-induced hepatocyte caspase-3/7 activity, and apoptosis as assessed by fluorometric assay and TdT-mediated dUTP nick-end labeling (TUNEL) staining, respectively. This effect was diminished in conditioned media from macrophages with IL-22 knockdown. Cytokine analysis in sera samples of patients with AH revealed that IL-22 levels were significantly elevated compared with healthy controls and heavy-drinking controls, implying a state of IL-22 resistance in human AH. Macrophage-derived IL-22 protects hepatocytes from ethanol-induced cell death. IL-22 downregulation is a new regulatory target of LPS in the pathogenesis of AH.

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KW - JNK

KW - Liver

KW - Macrophage

KW - MAPK

KW - SP600125

KW - Th17

KW - TUNEL

KW - U0126

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