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Induction of polymorphonuclear leukocyte-derived hepatocyte stimulating factor and effects on alpha 2-macroglobulin
H Ishibashi1, S Kurokawa, Y Tsuchiya
1First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Japan.
Abstract:
We investigated the kinetics of production of the hepatocyte stimulating factor (HSF) by peritoneal exudate- and peripheral circulating blood-polymorphonuclear leukocytes (PMNLs). Effects of the HSFs on alpha-2-macroglobulin (a2M) synthesis and a2M specific gene expression in primary cultured adult rat hepatocytes were also examined. Peritoneal exudate-PMNLs were collected 3 hr after the injection of alkaline-denatured casein into the peritoneal cavity of rats. Secretion of HSF into the culture medium began within 15 min after the start of incubation and practically a full secretion was noted within 3 hr. Lipopolysaccharide or other agents were not required to induce HSF from the PMNLs. Inhibitors of protein or DNA synthesis, cycloheximide, actinomycin D or puromycin, did not inhibit the secretion of HSF by rat PMNLs thereby suggesting that preformed and pooled HSF in the PMNLs was secreted during incubation. Peripheral circulating blood-PMNLs collected from a healthy man did not secrete HSF, in the absence of stimulation but did secrete HSF after vigorous agitation during incubation at 37 degrees C. The PMNL-HSF induced the synthesis of a2M and the accumulation of a2M mRNA in primary cultured rat hepatocytes. However, the effect was evident only with dexamethasone present in the culture medium. Furthermore, the effects of the PMNL-HSFs on a2M and albumin protein synthesis were reciprocal: The PMNL-HSF induced a2M synthesis, whereas it suppressed albumin synthesis.
Insights
Hepatocyte stimulating factor (HSF) is rapidly secreted by polymorphonuclear leukocytes (PMNLs). This PMNL-derived HSF influences alpha-2-macroglobulin (a2M) synthesis and gene expression in rat hepatocytes, but only with dexamethasone.
Area of Science:
- Immunology
- Molecular Biology
- Hepatology
Background:
- Polymorphonuclear leukocytes (PMNLs) are key immune cells involved in inflammatory responses.
- Hepatocyte stimulating factor (HSF) is a cytokine that influences liver cell function.
- Alpha-2-macroglobulin (a2M) is a major plasma proteinase inhibitor with diverse biological roles.
Purpose of the Study:
- To investigate the kinetics of HSF production by PMNLs.
- To examine the effects of PMNL-derived HSF on a2M synthesis and gene expression in hepatocytes.
- To determine the conditions required for HSF secretion and its impact on hepatocyte protein synthesis.
Main Methods:
- Collection and incubation of peritoneal exudate- and peripheral blood-PMNLs from rats and humans.
- Measurement of HSF secretion kinetics.
- Treatment of primary cultured adult rat hepatocytes with PMNL-HSF, with and without dexamethasone.
- Analysis of a2M and albumin synthesis and a2M mRNA levels.
Main Results:
- Peritoneal exudate-PMNLs secreted HSF within 15 minutes of incubation without additional stimulation.
- Peripheral blood-PMNLs secreted HSF upon vigorous agitation.
- PMNL-HSF induced a2M synthesis and mRNA accumulation in hepatocytes, but only in the presence of dexamethasone.
- PMNL-HSF exhibited reciprocal effects on protein synthesis, inducing a2M while suppressing albumin.
Conclusions:
- PMNLs can rapidly secrete preformed HSF.
- PMNL-derived HSF plays a role in regulating a2M synthesis in hepatocytes, modulated by dexamethasone.
- HSF influences the balance of acute-phase protein synthesis in the liver.