Norepinephrine modulates the growth‐inhibitory effect of transforming growth factor‐beta in primary rat hepatocyte cultures

Houck, Keith A.; Cruise, Jennifer L.; Michalopoulos, George K.

doi:10.1002/jcp.1041350327

Cited by 75 publications

(42 citation statements)

References 27 publications

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“…Hepatocytes, however, are the major site for clearance of circulating TGF,8 from plasma (20 in tissue culture but also in vivo (21). We have shown in previous studies that norepinephrine, acting through the a1-adrenergic receptor, enhances the mitogenic effect of EGF (and HPTA) while it suppresses the mitoinhibitory effect of TGF,8 (22). It has also been shown by other workers that some of the early biochemical changes seen within 2 hr after partial hepatectomy [hyperpolarization of the plasma membrane (23), glycogenolysis (24), increase of diacylglycerols (25), and the down-regulation of the EGF receptor (26)] are explainable by stimulation of the a1-adrenergic receptor.…”

Section: Resultsmentioning

confidence: 97%

Tissue distribution of hepatopoietin-A: a heparin-binding polypeptide growth factor for hepatocytes.

Zarnegar

Muga

Rahija

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

125

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Hepatopoietin-A (HPTA) is a heparinbinding polypeptide growth factor which consists of a heavy and a light polypeptide chain with molecular weights of 70,000 and 35,000, respectively. It stimulates DNA synthesis in primary cultures of normal rat hepatocytes in serum-free medium. The complete purification and characterization of HPTA from rabbit serum were reported by us elsewhere. Recently we have determined the amino-terminal amino acid sequence of the rabbit HPTA light chain up to 24 residues and have shown that the sequence is not homologous with other known sequences. [N.B. Human hepatocyte growth factor, recently sequenced by two other groups, is the same molecular species as HPTA.] In the present paper we report the production of a neutralizing polyclonal antiserum raised in chicken against purified rabbit HPTA. This antiserum does not inhibit the mitogenic effect of other potent inducers of hepatocyte DNA synthesis (epidermal growth factor or acidic fibroblast growth factor), nor does it interact with these growth factors in an enzyme-linked immunosorbent assay (ELISA). The antibody recognizes HPTA, as was determined by Western immunoblotting. Since the tissue origin of HPTA is not known, this anti-HPTA antiserum was used to investigate the tissue distribution of HPTA in rabbits by immunohistostaining methods. Acinar cells of the pancreas, neurons of the brain, C cells of the thyroid, ductal cells of the salivary glands, and Brunners glands of the duodenum stained with anti-HPTA antibody. Liver, spleen, thymus, and kidney do not seem to contain appreciable amounts of HPTA. We confirmed these fin gs by extracting and purifying active HPTA from the stained tissues listed above. The anti-HPTA antibody recognizes HPTA purifiled from different tissues, as was determined by ELISA, Western immunoblotting, and immunoneutralization experiments. We have also determined the sequence of the first 24 amino acids of the amino terminus of the light chain of rabbit HPITA and have shown that there is no homology between this sequence and the sequences of any known proteins and polypeptide growth factors (7). Growth factors with properties similar to those of HPTA have also been purified from human plasma or rat platelets by others (8,9).In the present paper we describe the production of a neutralizing polyclonal antibody raised in chicken against purified rabbit HPTA and the establishment of an enzymelinked immunosorbent assay (ELISA) for detection of nanogram quantities of this growth factor. This antiserum was used to investigate the tissue distribution of HPTA in rabbits. MATERIALS AND METHODSExtraction and Purification of HPTA from Different Rabbit Tissues. Rabbit pancreas, thyroid, pituitary, submaxillary gland, parotid gland, intestinal mucosa, spleen, and brain (from 25-50 rabbits) were purchased from Pel-Freez Biologicals. Frozen tissues were homogenized in extraction buffer consisting of phosphate-buffered saline (PBS; NaCI, 8.8 g/l; NaH2PO4 H2O, 0.2 g/l; Na2HPO4, 1.4 g/l), pH 7.4, containing 1 mM phenylm...

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Section: Resultsmentioning

confidence: 97%

Tissue distribution of hepatopoietin-A: a heparin-binding polypeptide growth factor for hepatocytes.

Zarnegar

Muga

Rahija

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

125

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“…Other substances released locally and in the peripheral circulation shortly (within 1 h) after PHx are hyaluronic acid (a major component of hepatic biomatrix) and TGFb1 (Michalopoulos and DeFrances, 1997). TGFb1 is a known hepatocyte mito-inhibitor (Houck et al, 1988). When the receptor TGFbR1 is rendered inactive in normal, non-regenerating liver by injecting dominant negative DNA constructs, there is a noticeable increase in DNA synthesis of hepatocytes (Ichikawa et al, 2001).…”

Section: Early Events Occurring In Liver After Phxmentioning

confidence: 99%

“…Epinephrine and norepinephrine are released in peripheral circulation from nerve endings, as well as from the adrenal medulla. Interest in the role of norepinephrine in liver regeneration arose when it was shown that norepinephrine substantially enhances the mitogenic effects of EGF and HGF in hepatocyte cultures and it decreases the mito-inhibitory effects of TGFb1 (Cruise et al, 1985;Houck et al, 1988). In cultures of hepatocytes with balanced concentrations of EGF and TGFb1 such that the final effect is neutral (EGF mitogenic effect is balanced by the mito-inhibitory effect of TGFb1), addition of norepinephrine triggers high-level hepatocyte DNA synthesis (Houck and Michalopoulos, 1989).…”

Section: Norepinephrinementioning

confidence: 99%

Liver regeneration

Michalopoulos

2007

Journal Cellular Physiology

1,331

1,224

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Liver regeneration after partial hepatectomy is a very complex and well-orchestrated phenomenon. It is carried out by the participation of all mature liver cell types. The process is associated with signaling cascades involving growth factors, cytokines, matrix remodeling, and several feedbacks of stimulation and inhibition of growth related signals. Liver manages to restore any lost mass and adjust its size to that of the organism, while at the same time providing full support for body homeostasis during the entire regenerative process. In situations when hepatocytes or biliary cells are blocked from regeneration, these cell types can function as facultative stem cells for each other.

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“…TGFj expression in normal and neoplastic tissues. TGFP is a strong inhibitor of the proliferation of epithelial cells, including hepatocytes (22), but it can have different effects, depending on what other factors are present (40). TGF, is known to antagonize the mitogenic effects of stimulating growth factors, such as the effects of fibroblast growth factor on vascular endothelial cells (21) or the effects of epidermal growth factor on hepatocytes (22) or on myc-transfected fibroblasts (40).…”

Section: Discussionmentioning

confidence: 99%

Heparin and hormonal regulation of mRNA synthesis and abundance of autocrine growth factors: relevance to clonal growth of tumors.

Zvibel¹,

Halay²,

Reíd³

1991

Mol. Cell. Biol.

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Highly sulfated, heparinlike species of heparan sulfate proteoglycans, with heparinlike glycosaminoglycan chains, are extracellular matrix components that are plasma membrane bound in growth-arrested liver cells. Heparins were found to inhibit the growth and lower the clonal growth efficiency of HepG2, a minimally deviant, human hepatoma cell line. Heparan sulfates, closely related glycosaminoglycans present in the extracellular matrix around growing liver cells, had no effect on the growth rate or clonal growth efficiency of HepG2 cells. Neither heparins nor heparan sulfates had any effect on the growth rate or clonal growth efficiency of two poorly differentiated, highly metastatic hepatoma cell lines, SK-Hep-l and PLC/PRF/5. Heparin's inhibition of growth of HepG2 cells correlated with changes in the mRNA synthesis and abundance of insulinlike growth factor II (IGF II) and transforming growth factor beta (TGF,I). HepG2 cells expressed high basal levels of mRNAs encoding IGF II and TGFP that were inducible, through transcriptional and posttranscriptional mechanisms, to higher levels by specific heparin-hormone combinations. For both IGF II and TGF,, the regulation was multifactorial. Transcriptionally, IGF II was regulated by the additive effects of insulin, glucagon, and growth hormone in combination with heparin; TGF(i was regulated primarily by the synergistic effects of insulin and growth hormone in combination with heparin. Posttranscriptionally, the mRNA abundance of the IGF II 4.5-and 3.7-kb transcripts was affected by insulin. Heparin induction of all IGF II transcripts was also dependent on triiodotyronine and prolactin, but it is unknown whether their induction by heparin was via transcriptional or posttranscriptional mechanisms. Heparin-insulin combinations regulated TGFPi posttranscriptionally. The poorly differentiated hepatoma cell lines PLC/PRF/5 and SK-Hep-l either did not express or constitutively expressed low basal levels of IGF I, IGF II, and TGFIA, whose mRNA synthesis and abundance showed no response to any heparin-hormone combination. We discuss the data as evidence that matrix chemistry is a variable determining the expression of autocrine growth factor genes and the biological responses to them.Previous studies from our laboratory (10) have indicated that the extracellular matrix contains a set of factors affecting the clonal growth efficiency of tumor cells, a characteristic important for the ability of tumor cells to metastasize and colonize specific tissues. The matrix components responsible for this phenomenon include species of highly sulfated, heparinlike heparan sulfate proteoglycans or their glycosaminoglycan chains, heparinlike heparan sulfates (10). We are now trying to elucidate the mechanism by which heparins and heparinlike heparan sulfates or their proteoglycan forms can differentially affect the clonal growth efficiency of metastatic versus nonmetastatic carcinomas. Our working hypothesis, tested in these studies, has been that these heparins or heparinlike molecules reg...

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Norepinephrine modulates the growth‐inhibitory effect of transforming growth factor‐beta in primary rat hepatocyte cultures

Cited by 75 publications

References 27 publications

Tissue distribution of hepatopoietin-A: a heparin-binding polypeptide growth factor for hepatocytes.

Tissue distribution of hepatopoietin-A: a heparin-binding polypeptide growth factor for hepatocytes.

Liver regeneration

Heparin and hormonal regulation of mRNA synthesis and abundance of autocrine growth factors: relevance to clonal growth of tumors.

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