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Interleukin-22 may mitigate nonalcoholic fatty liver disease (NAFLD)–related fibrosis in females but not males, suggesting a sex-linked hepatoprotective pathway, according to investigators.
These differences between men and women should be considered when conducting clinical trials for IL-22–targeting therapies, reported lead author Mohamed N. Abdelnabi, MSc, of the Centre de Recherche du Centre Hospitalier de l’Université de Montréal and colleagues.
“IL-22 is a pleiotropic cytokine with both inflammatory and protective effects during injury and repair in various tissues including the liver,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology, noting that IL-22 activity has been linked with both antifibrotic and profibrotic outcomes in previous preclinical studies. “These different observations highlight the dual nature of IL-22 that likely is dictated by multiple factors including the tissue involved, pathologic environment, endogenous vs. exogenous IL-22 level, and the time of exposure.”
Prior research has left some questions unanswered, the investigators noted, because many studies have relied on exogenous administration of IL-22 in mouse models, some of which lack all the metabolic abnormalities observed in human disease. Furthermore, these mice were all male, which has prevented detection of possible sex-linked differences in IL-22–related pathophysiology, they added.
To address these gaps, the investigators conducted a series of experiments involving men and women with NAFLD, plus mice of both sexes with NAFLD induced by a high-fat diet, both wild-type and with knock-out of the IL-22 receptor.
Human data
To characterize IL-22 activity in men versus women with NAFLD, the investigators first analyzed two publicly available microarray datasets. These revealed notably increased expression of hepatic IL-22 mRNA in the livers of females compared with males. Supporting this finding, liver biopsies from 11 men and 9 women with NAFLD with similar levels of fibrosis showed significantly increased IL-22–producing cells in female patients compared with male patients.
“These results suggest a sexual dimorphic expression of IL-22 in the context of NAFLD,” the investigators wrote.
Mouse data
Echoing the human data, the livers of female wild-type mice with NAFLD had significantly greater IL-22 expression than male mice at both mRNA and protein levels.
Next, the investigators explored the effects of IL-22–receptor knockout. In addition to NAFLD, these knockout mice developed weight gain and metabolic alterations, especially insulin resistance, supporting previous work that highlighted the protective role of IL-22 against these outcomes. More relevant to the present study, female knockout mice had significantly worse hepatic liver injury, apoptosis, inflammation, and fibrosis than male knockout mice, suggesting that IL-22 signaling confers hepatoprotection in females but not males.
“These observations may suggest a regulation of IL-22 expression by the female sex hormone estrogen,” the investigators wrote. “Indeed, estrogen is known to modulate inflammatory responses in NAFLD, but the underlying mechanisms remain undefined. ... Further in vivo studies are warranted to investigate whether endogenous estrogen regulates hepatic IL-22 expression in the context of NAFLD.”
In the meantime, the present data may steer drug development.
“These findings should be considered in clinical trials testing IL-22–based therapeutic approaches in treatment of female vs. male subjects with NAFLD,” the investigators concluded.
The study was partially funded by the Canadian Liver Foundation and the Canadian Institutes of Health Research, the Bourse d’Exemption des Droits de Scolarité Supplémentaires from the Université de Montréal, the Canadian Network on Hepatitis, and others. The investigators disclosed no competing interests.
The cytokine interleukin-22 has potential as a therapeutic for nonalcoholic fatty liver disease, as it has been shown to decrease fat accumulation in hepatocytes and has various other liver protective effects such as prevention of cell death, enhancement of proliferation, and, importantly, reduction of liver fibrosis progression. Indeed, a recombinant derivative of IL22 has been studied in a clinical trial of alcoholic liver disease and has been found to be safe. However, the beneficial effect of this cytokine is context dependent. High levels of IL22 increased inflammation or fibrosis in hepatitis B infection and in toxic injury models in mouse models.
This is in line with observations that progression to cirrhosis in NAFLD is greater after menopause. On the other hand, women are more likely to develop cirrhosis than men despite higher levels of IL22, indicating more factors are at play in the progression of NAFLD. Overall, this report should alert investigators to consider the sex-specific effects of emerging therapies for NAFLD. Future IL22-based trials must include sex-based subgroup analyses.
Kirk Wangensteen, MD, PhD, is with the department of medicine, division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn. He declares no relevant conflicts of interest.
The cytokine interleukin-22 has potential as a therapeutic for nonalcoholic fatty liver disease, as it has been shown to decrease fat accumulation in hepatocytes and has various other liver protective effects such as prevention of cell death, enhancement of proliferation, and, importantly, reduction of liver fibrosis progression. Indeed, a recombinant derivative of IL22 has been studied in a clinical trial of alcoholic liver disease and has been found to be safe. However, the beneficial effect of this cytokine is context dependent. High levels of IL22 increased inflammation or fibrosis in hepatitis B infection and in toxic injury models in mouse models.
This is in line with observations that progression to cirrhosis in NAFLD is greater after menopause. On the other hand, women are more likely to develop cirrhosis than men despite higher levels of IL22, indicating more factors are at play in the progression of NAFLD. Overall, this report should alert investigators to consider the sex-specific effects of emerging therapies for NAFLD. Future IL22-based trials must include sex-based subgroup analyses.
Kirk Wangensteen, MD, PhD, is with the department of medicine, division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn. He declares no relevant conflicts of interest.
The cytokine interleukin-22 has potential as a therapeutic for nonalcoholic fatty liver disease, as it has been shown to decrease fat accumulation in hepatocytes and has various other liver protective effects such as prevention of cell death, enhancement of proliferation, and, importantly, reduction of liver fibrosis progression. Indeed, a recombinant derivative of IL22 has been studied in a clinical trial of alcoholic liver disease and has been found to be safe. However, the beneficial effect of this cytokine is context dependent. High levels of IL22 increased inflammation or fibrosis in hepatitis B infection and in toxic injury models in mouse models.
This is in line with observations that progression to cirrhosis in NAFLD is greater after menopause. On the other hand, women are more likely to develop cirrhosis than men despite higher levels of IL22, indicating more factors are at play in the progression of NAFLD. Overall, this report should alert investigators to consider the sex-specific effects of emerging therapies for NAFLD. Future IL22-based trials must include sex-based subgroup analyses.
Kirk Wangensteen, MD, PhD, is with the department of medicine, division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn. He declares no relevant conflicts of interest.
Interleukin-22 may mitigate nonalcoholic fatty liver disease (NAFLD)–related fibrosis in females but not males, suggesting a sex-linked hepatoprotective pathway, according to investigators.
These differences between men and women should be considered when conducting clinical trials for IL-22–targeting therapies, reported lead author Mohamed N. Abdelnabi, MSc, of the Centre de Recherche du Centre Hospitalier de l’Université de Montréal and colleagues.
“IL-22 is a pleiotropic cytokine with both inflammatory and protective effects during injury and repair in various tissues including the liver,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology, noting that IL-22 activity has been linked with both antifibrotic and profibrotic outcomes in previous preclinical studies. “These different observations highlight the dual nature of IL-22 that likely is dictated by multiple factors including the tissue involved, pathologic environment, endogenous vs. exogenous IL-22 level, and the time of exposure.”
Prior research has left some questions unanswered, the investigators noted, because many studies have relied on exogenous administration of IL-22 in mouse models, some of which lack all the metabolic abnormalities observed in human disease. Furthermore, these mice were all male, which has prevented detection of possible sex-linked differences in IL-22–related pathophysiology, they added.
To address these gaps, the investigators conducted a series of experiments involving men and women with NAFLD, plus mice of both sexes with NAFLD induced by a high-fat diet, both wild-type and with knock-out of the IL-22 receptor.
Human data
To characterize IL-22 activity in men versus women with NAFLD, the investigators first analyzed two publicly available microarray datasets. These revealed notably increased expression of hepatic IL-22 mRNA in the livers of females compared with males. Supporting this finding, liver biopsies from 11 men and 9 women with NAFLD with similar levels of fibrosis showed significantly increased IL-22–producing cells in female patients compared with male patients.
“These results suggest a sexual dimorphic expression of IL-22 in the context of NAFLD,” the investigators wrote.
Mouse data
Echoing the human data, the livers of female wild-type mice with NAFLD had significantly greater IL-22 expression than male mice at both mRNA and protein levels.
Next, the investigators explored the effects of IL-22–receptor knockout. In addition to NAFLD, these knockout mice developed weight gain and metabolic alterations, especially insulin resistance, supporting previous work that highlighted the protective role of IL-22 against these outcomes. More relevant to the present study, female knockout mice had significantly worse hepatic liver injury, apoptosis, inflammation, and fibrosis than male knockout mice, suggesting that IL-22 signaling confers hepatoprotection in females but not males.
“These observations may suggest a regulation of IL-22 expression by the female sex hormone estrogen,” the investigators wrote. “Indeed, estrogen is known to modulate inflammatory responses in NAFLD, but the underlying mechanisms remain undefined. ... Further in vivo studies are warranted to investigate whether endogenous estrogen regulates hepatic IL-22 expression in the context of NAFLD.”
In the meantime, the present data may steer drug development.
“These findings should be considered in clinical trials testing IL-22–based therapeutic approaches in treatment of female vs. male subjects with NAFLD,” the investigators concluded.
The study was partially funded by the Canadian Liver Foundation and the Canadian Institutes of Health Research, the Bourse d’Exemption des Droits de Scolarité Supplémentaires from the Université de Montréal, the Canadian Network on Hepatitis, and others. The investigators disclosed no competing interests.
Interleukin-22 may mitigate nonalcoholic fatty liver disease (NAFLD)–related fibrosis in females but not males, suggesting a sex-linked hepatoprotective pathway, according to investigators.
These differences between men and women should be considered when conducting clinical trials for IL-22–targeting therapies, reported lead author Mohamed N. Abdelnabi, MSc, of the Centre de Recherche du Centre Hospitalier de l’Université de Montréal and colleagues.
“IL-22 is a pleiotropic cytokine with both inflammatory and protective effects during injury and repair in various tissues including the liver,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology, noting that IL-22 activity has been linked with both antifibrotic and profibrotic outcomes in previous preclinical studies. “These different observations highlight the dual nature of IL-22 that likely is dictated by multiple factors including the tissue involved, pathologic environment, endogenous vs. exogenous IL-22 level, and the time of exposure.”
Prior research has left some questions unanswered, the investigators noted, because many studies have relied on exogenous administration of IL-22 in mouse models, some of which lack all the metabolic abnormalities observed in human disease. Furthermore, these mice were all male, which has prevented detection of possible sex-linked differences in IL-22–related pathophysiology, they added.
To address these gaps, the investigators conducted a series of experiments involving men and women with NAFLD, plus mice of both sexes with NAFLD induced by a high-fat diet, both wild-type and with knock-out of the IL-22 receptor.
Human data
To characterize IL-22 activity in men versus women with NAFLD, the investigators first analyzed two publicly available microarray datasets. These revealed notably increased expression of hepatic IL-22 mRNA in the livers of females compared with males. Supporting this finding, liver biopsies from 11 men and 9 women with NAFLD with similar levels of fibrosis showed significantly increased IL-22–producing cells in female patients compared with male patients.
“These results suggest a sexual dimorphic expression of IL-22 in the context of NAFLD,” the investigators wrote.
Mouse data
Echoing the human data, the livers of female wild-type mice with NAFLD had significantly greater IL-22 expression than male mice at both mRNA and protein levels.
Next, the investigators explored the effects of IL-22–receptor knockout. In addition to NAFLD, these knockout mice developed weight gain and metabolic alterations, especially insulin resistance, supporting previous work that highlighted the protective role of IL-22 against these outcomes. More relevant to the present study, female knockout mice had significantly worse hepatic liver injury, apoptosis, inflammation, and fibrosis than male knockout mice, suggesting that IL-22 signaling confers hepatoprotection in females but not males.
“These observations may suggest a regulation of IL-22 expression by the female sex hormone estrogen,” the investigators wrote. “Indeed, estrogen is known to modulate inflammatory responses in NAFLD, but the underlying mechanisms remain undefined. ... Further in vivo studies are warranted to investigate whether endogenous estrogen regulates hepatic IL-22 expression in the context of NAFLD.”
In the meantime, the present data may steer drug development.
“These findings should be considered in clinical trials testing IL-22–based therapeutic approaches in treatment of female vs. male subjects with NAFLD,” the investigators concluded.
The study was partially funded by the Canadian Liver Foundation and the Canadian Institutes of Health Research, the Bourse d’Exemption des Droits de Scolarité Supplémentaires from the Université de Montréal, the Canadian Network on Hepatitis, and others. The investigators disclosed no competing interests.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY