EFFECT OF INFLAMMATORY CYTOKINES ON HYPOXIA-INDUCED ERYTHROPOIETIN PRODUCTION

The effects of the inflammatory cytokines interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, transforming growth factor-beta (TGF-beta), and tumor necrosis factor-alpha (TNF-alpha) on erythropoietin (Epo) production in Hep3B cells were examined. The addition of IL-1 alpha, IL-1 beta, or TNF-alpha resulted in a dose-dependent inhibition of hypoxia-induced Epo production by as much as 89%. IL-1 beta was the most effective cytokine tested, demonstrating half-maximal inhibition at 0.4 U/mL compared with 1.0 and 10.0 U/mL for IL-1 alpha and TNF-alpha, respectively. TGF-beta also inhibited hypoxia-induced Epo production, but only by as much as 56%. In contrast to IL-1 alpha, IL-1 beta, TNF-alpha, and TGF-beta, the addition of IL-6 to hypoxic Hep3B cells resulted in a dose-dependent stimulation of hypoxia-induced Epo production by as much as 81%. However, IL-6 did not stimulate Epo synthesis in the absence of hypoxia, and was thus synergistic with hypoxia in inducing Epo production. Combinations of IL-1 alpha, TNF-alpha, and IL-6 were found to be additive in their effects on hypoxia-induced Epo production. By Northern blot analysis, Epo messenger RNA levels in Hep3B cells grown in 1% O2 were decreased when concurrently exposed to either IL-1 alpha or TNF-alpha. The effects that IL-1 alpha, IL-1 beta, TGF-beta, TNF-alpha, and IL-6 have on hypoxia-induced Epo production may provide new insights into the signal transduction pathway by which hypoxia leads to changes in gene expression. In addition, the effects of these inflammatory cytokines on hypoxia-induced Epo production in vitro suggest that in various inflammatory disorders these cytokines may affect Epo production in vivo and may play a significant role in the pathogenesis of the anemia of chronic disease.

[1]  P. Ratcliffe,et al.  Organ distribution of erythropoietin messenger RNA in normal and uremic rats. , 1991, Kidney international.

[2]  J. Caro,et al.  Functional analysis of the erythropoietin gene reveals hypoxia responsive element at the 3 flanking region , 1991 .

[3]  M. Goldberg,et al.  Erythropoietin mRNA levels are governed by both the rate of gene transcription and posttranscriptional events. , 1991, Blood.

[4]  J. Egrie,et al.  The erythropoietic effects of interleukin 6 and erythropoietin in vivo. , 1991, Experimental hematology.

[5]  M. Goldberg,et al.  Serum erythropoietin levels in patients receiving intensive chemotherapy and radiotherapy. , 1990, Blood.

[6]  T. Schnitzer,et al.  Multicenter study of recombinant human erythropoietin in correction of anemia in rheumatoid arthritis. , 1990, The American journal of medicine.

[7]  E. Dessypris,et al.  Inhibition of human colony-forming-unit erythroid by tumor necrosis factor requires accessory cells. , 1990, The Journal of clinical investigation.

[8]  H. Fillit,et al.  Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. , 1990, The New England journal of medicine.

[9]  M. Sporn,et al.  Suppression of experimental glomerulonephritis by antiserum against transforming growth factor β1 , 1990, Nature.

[10]  G. Bakris,et al.  Effects of theophylline on erythropoietin production in normal subjects and in patients with erythrocytosis after renal transplantation. , 1990, The New England journal of medicine.

[11]  R. Weinmann,et al.  Enhancement by hypoxia of human erythropoietin gene transcription in vitro. , 1990, The Journal of biological chemistry.

[12]  S. Piantadosi,et al.  Decreased erythropoietin response in patients with the anemia of cancer. , 1990, The New England journal of medicine.

[13]  H. Gisslinger,et al.  Erythropoietin treatment of anemia associated with multiple myeloma. , 1990, The New England journal of medicine.

[14]  S. Akira,et al.  A nuclear factor for IL‐6 expression (NF‐IL6) is a member of a C/EBP family. , 1990, The EMBO journal.

[15]  L. Bonewald,et al.  Erythropoietin fails to reverse the anemia in mice continuously exposed to tumor necrosis factor-alpha in vivo. , 1990, Experimental hematology.

[16]  M. Fischl,et al.  Recombinant human erythropoietin for patients with AIDS treated with zidovudine. , 1990, The New England journal of medicine.

[17]  T. Ulich,et al.  Tumor necrosis factor exerts dose-dependent effects on erythropoiesis and myelopoiesis in vivo. , 1990, Experimental hematology.

[18]  S. Antonarakis,et al.  Human erythropoietin gene expression in transgenic mice: multiple transcription initiation sites and cis-acting regulatory elements , 1990, Molecular and cellular biology.

[19]  P. Furmanski,et al.  In vivo suppression of erythropoiesis by tumor necrosis factor-alpha (TNF-alpha): reversal with exogenous erythropoietin (EPO). , 1990, Experimental hematology.

[20]  W. Jelkmann,et al.  Immunoreactive erythropoietin in the anemia of non-renal chronic diseases. , 1990, Biomedica biochimica acta.

[21]  R. Cortese,et al.  Interleukin 6 induces a liver-specific nuclear protein that binds to the promoter of acute-phase genes. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[22]  W. Jelkmann,et al.  Erythropoietin/haemoglobin relationship in leukaemia and ulcerative colitis , 1989, European journal of haematology.

[23]  T. Quinn,et al.  Serum immunoreactive erythropoietin in HIV-infected patients. , 1989, JAMA.

[24]  T. Pincus,et al.  Treatment of the anemia of rheumatoid arthritis with recombinant human erythropoietin: clinical and in vitro studies. , 1989, Arthritis and rheumatism.

[25]  P. Brandtzaeg,et al.  Brief Definitive Report the Complex Pattern of Cytokines in Serum from Patients with Meningococcal Septic Shock Association between Interleukin 6, Interleukin 1, and Fatal Outcome , 2022 .

[26]  R. Weinmann,et al.  Stimulation of erythropoietin gene transcription during hypoxia and cobalt exposure. , 1989, Blood.

[27]  T. Ulich,et al.  In vivo hematologic effects of recombinant interleukin-6 on hematopoiesis and circulating numbers of RBCs and WBCs. , 1989, Blood.

[28]  M. Goldberg,et al.  Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein. , 1988, Science.

[29]  K. Bendtzen.  Interleukin 1, interleukin 6 and tumor necrosis factor in infection, inflammation and immunity. , 1988, Immunology letters.

[30]  M. Hochberg,et al.  Serum immunoreactive erythropoietin in rheumatoid arthritis: impaired response to anemia. , 1988, Arthritis and rheumatism.

[31]  R. Cortese,et al.  Recombinant interleukin 6 regulates the transcriptional activation of a set of human acute phase genes. , 1988, The Journal of biological chemistry.

[32]  C. Maury,et al.  Elevated levels of circulating cachectin/tumor necrosis factor in patients with acquired immunodeficiency syndrome. , 1988, The American journal of medicine.

[33]  D. Heinegård,et al.  Detection of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum. , 1988, Arthritis and rheumatism.

[34]  H. Colten,et al.  Acute phase reactants in inflammation and infection. , 1988, Seminars in hematology.

[35]  L. Aarden,et al.  Interleukin 6 (IL-6) in serum and urine of renal transplant recipients. , 1988, Clinical and experimental immunology.

[36]  F. Houssiau,et al.  Elevated levels of the 26K human hybridoma growth factor (interleukin 6) in cerebrospinal fluid of patients with acute infection of the central nervous system. , 1988, Clinical and experimental immunology.

[37]  J. Tavernier,et al.  EVIDENCE FOR TUMOUR NECROSIS FACTOR/CACHECTIN PRODUCTION IN CANCER , 1987, The Lancet.

[38]  M A Goldberg,et al.  The regulated expression of erythropoietin by two human hepatoma cell lines. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[39]  C. Hack,et al.  SERUM LEVELS OF INTERLEUKIN-6 AND ACUTE PHASE RESPONSES , 1987, The Lancet.

[40]  P. Lansdorp,et al.  Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[41]  A. Allison,et al.  Inhibition by interleukin-1 of the action of erythropoietin on erythroid precursors and its possible role in the pathogenesis of hypoplastic anaemias. , 1987 .

[42]  T. Hirano,et al.  Recombinant human B cell stimulatory factor 2 (BSF‐2/IFN‐β2) regulates β‐fibrinogen and albumin mRNA levels in Fao‐9 cells , 1987 .

[43]  E. Goldwasser,et al.  Blunted erythropoietin response to anaemia in rheumatoid arthritis , 1987, British journal of haematology.

[44]  J. Adamson,et al.  Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. , 1987, The New England journal of medicine.

[45]  E. Goldwasser,et al.  Expression of the erythropoietin gene. , 1986, Blood cells.

[46]  H. Colten,et al.  Cachectin/tumor necrosis factor regulates hepatic acute-phase gene expression. , 1986, The Journal of clinical investigation.

[47]  D. R. Wilson,et al.  Monocyte-conditioned medium, interleukin-1, and tumor necrosis factor stimulate the acute phase response in human hepatoma cells in vitro , 1986, The Journal of cell biology.

[48]  M. Koury,et al.  Anemia induces accumulation of erythropoietin mRNA in the kidney and liver. , 1986, Molecular and cellular biology.

[49]  S. Zucker.  Anemia in cancer. , 1985, Cancer investigation.

[50]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[51]  A. Feinberg,et al.  A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. , 1983, Analytical biochemistry.

[52]  W. Bennett,et al.  Postrenal transplant erythrocytosis: a review of 53 patients. , 1983, Kidney international.

[53]  Lee Gr.  The anemia of chronic disease. , 1983, Seminars in hematology.

[54]  E. Cronkite,et al.  Further evidence of the in vivo role of erythropoietin or companion molecules induced by hypoxia on proliferation and continuing differentiation of BFU-e in PCDC. , 1981, Blood.

[55]  W. Rutter,et al.  Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. , 1979, Biochemistry.

[56]  S. Zucker,et al.  The Anaemia of Chronic Disorders: Studies of Iron Reutilization in the Anaemia of Experimental Malignancy and Chronic Inflammation , 1977, British journal of haematology.

[57]  E. Zanjani,et al.  Liver as the primary site of erythropoietin formation in the fetus. , 1977, The Journal of laboratory and clinical medicine.

[58]  J. Adamson,et al.  The anemia of chronic disorders: studies of marrow regulation and iron metabolism , 1975 .

[59]  V. E. Price,et al.  Anemia in cancer. , 1958, Advances in cancer research.

[60]  E. Goldwasser,et al.  Role of the Kidney in Erythropoiesis , 1957, Nature.