Hypoferraemia during the early inflammatory response is dependent on tumour necrosis factor activity in a murine model of protracted peritonitis

Schubert,Thomas  E.O.; Bosserhoff,Anja   K.; Peyssonaux,Carole; Echtenacher,Bernd; Knutson,Mitchell; Hofstädter,Ferdinand; Männel,Daniela  N.

doi:10.3892/mmr.2012.1004

Hypoferraemia during the early inflammatory response is dependent on tumour necrosis factor activity in a murine model of protracted peritonitis

Authors:
- Thomas E.O. Schubert
- Anja K. Bosserhoff
- Carole Peyssonaux
- Bernd Echtenacher
- Mitchell Knutson
- Ferdinand Hofstädter
- Daniela N. Männel
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Affiliations: Institute of Applied Pathology, Speyer, Germany, Department of Pathology, University of Regensburg, Regensburg, Germany, Department of Endocrinology, Metabolism and Cancer, INSERM U567, Faculty Cochin, Paris, France, Department of Immunology, University of Regensburg, Regensburg, Germany, Food Science and Human Nutrition Department, University of Florida, Gainesville, Florida, USA
Published online on: July 24, 2012 https://doi.org/10.3892/mmr.2012.1004
Pages: 838-842

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Abstract

On the grounds of clinical, in vitro and in vivo studies, tumour necrosis factor (TNF) is considered to be one of the inflammatory cytokines that contributes to to the generation of hypoferraemia and anaemia of inflammation (AI). We used a recently described murine model for AI and hypoferraemia, based on sublethal caecal ligation and puncture (CLP) with ensuing protracted peritonitis, to investigate the contribution of TNF to the generation of hypoferraemia. During the early inflammatory response to CLP, a marked decrease in serum iron concentration occurs within 8 h. To determine whether TNF contributes to the generation of hypoferraemia at this time point, we studied TNF-deficient mice and wild-type mice that underwent CLP. The serum iron concentration was decreased in wild-type mice whereas TNF-deficient mice maintained normal serum iron levels following CLP. Hypoferraemia in wild-type mice was accompanied by the downregulation of ferroportin 1 (Fp1) in macrophages. In the macrophages of TNF-deficient mice, Fp1 was not downregulated following CLP. The initial expression of hepcidin was detectable at the mRNA level but not at the protein level by immunohistochemistry in wild-type and TNF-deficient mice. Therefore, hepcidin does not appear to be involved in the regulation of early hypoferraemia. TNF appears to regulate the expression of Fp1 by transcriptional control. Our results demonstrate that TNF mediates hypoferraemia during the early inflammatory response by regulating the expression of Fp1 in macrophages.

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1	Weiss G: Modification of iron regulation by the inflammatory response (Review). Best Pract Res Clin Haematol. 18:183–201. 2005. View Article : Google Scholar : PubMed/NCBI
2	Schaible UE and Kaufmann SH: Iron and microbial infection. Nat Rev Microbiol. 2:946–953. 2004. View Article : Google Scholar : PubMed/NCBI
3	Laftah AH, Sharma N, Brookes MJ, McKie AT, Simpson RJ, Iqbal TH and Tselepis C: Tumour necrosis factor alpha causes hypoferraemia and reduced intestinal iron absorption in mice. Biochem J. 397:61–67. 2006. View Article : Google Scholar
4	Johnson RA, Waddelow TA, Caro J, Oliff A and Roodman GD: Chronic exposure to tumor necrosis factor in vivo preferentially inhibits erythropoiesis in nude mice. Blood. 74:130–138. 1989.PubMed/NCBI
5	Feelders RA, Vreugdenhil G, Eggermont AM, Kuiper-Kramer PA, van Eijk HG and Swaak AJ: Regulation of iron metabolism in the acute-phase response: interferon gamma and tumour necrosis factor alpha induce hypoferraemia, ferritin production and a decrease in circulating transferrin receptors in cancer patients. Eur J Clin Invest. 28:520–527. 1998. View Article : Google Scholar
6	Alvarez-Hernández X, Licéaga J, McKay IC and Brock JH: Induction of hypoferremia and modulation of macrophage iron metabolism by tumor necrosis factor. Lab Invest. 61:319–322. 1989.PubMed/NCBI
7	Sharma N, Laftah AH, Brookes MJ, Cooper B, Iqbal T and Tselepis C: A role for tumour necrosis factor alpha in human small bowel iron transport. Biochem J (Pt 2). 390:437–446. 2005.PubMed/NCBI
8	Ludwiczek S, Aigner E, Theurl I and Weiss G: Cytokine-mediated regulation of iron transport in human monocytic cells. Blood. 101:4148–4154. 2003. View Article : Google Scholar : PubMed/NCBI
9	Körner H, Cook M, Riminton DS, Lemckert FA, Hoek RM, Ledermann B, Köntgen F, Fazekas de St Groth B and Sedgwick JD: Distinct roles for lymphotoxin-alpha and tumor necrosis factor in organogenesis and spatial organization of lymphoid tissue. Eur J Immunol. 27:2600–2609. 1997.PubMed/NCBI
10	Schubert TE, Echtenacher B, Hofstädter F and Männel DN: Failure of interferon-γ and tumor necrosis factor in mediating anemia of chronic disease in a mouse model of protracted septic peritonitis. Int J Mol Med. 16:753–758. 2005.
11	Tanaka T, Araki E, Nitta K and Tateno M: Recombinant human tumor necrosis factor depresses serum iron in mice. J Biol Response Mod. 6:484–488. 1987.PubMed/NCBI
12	Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T and Kaplan J: Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 306:2090–2093. 2004. View Article : Google Scholar : PubMed/NCBI
13	Rivera S, Nemeth E, Gabayan V, Lopez MA, Farshidi D and Ganz T: Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs. Blood. 106:2196–2199. 2005. View Article : Google Scholar : PubMed/NCBI
14	Peyssonnaux C, Zinkernagel AS, Datta V, Lauth X, Johnson RS and Nizet V: TLR4-dependent hepcidin expression by myeloid cells in response to bacterial pathogens. Blood. 107:3727–3732. 2006. View Article : Google Scholar : PubMed/NCBI
15	Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, Beaumont C, Kahn A and Vaulont S: The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 110:1037–1044. 2002. View Article : Google Scholar : PubMed/NCBI
16	Nanami M, Ookawara T, Otaki Y, Ito K, Moriguchi R, Miyagawa K, Hasuike Y, Izumi M, Eguchi H, Suzuki K and Nakanishi T: Tumor necrosis factor-alpha-induced iron sequestration and oxidative stress in human endothelial cells. Arterioscler Thromb Vasc Biol. 25:2495–2501. 2005. View Article : Google Scholar : PubMed/NCBI
17	Liu XB, Nguyen NB, Marquess KD, Yang F and Haile DJ: Regulation of hepcidin and ferroportin expression by lipopolysaccharide in splenic macrophages. Blood Cells Mol Dis. 35:47–56. 2005. View Article : Google Scholar : PubMed/NCBI
18	Yang F, Liu XB, Quinones M, Melby PC, Ghio A and Haile DJ: Regulation of reticuloendothelial iron transporter MTP1 (Slc11a3) by inflammation. J Biol Chem. 277:39786–39791. 2002. View Article : Google Scholar : PubMed/NCBI
19	Schubert T, Echtenacher B, Hofstädter F and Männel DN: TNF-independent development of transient anemia of chronic disease in a mouse model of protracted septic peritonitis. Lab Invest. 83:1743–1750. 2003. View Article : Google Scholar : PubMed/NCBI
20	Ganz T and Nemeth E: Iron sequestration and anemia of inflammation. Semin Hematol. 46:387–393. 2009. View Article : Google Scholar : PubMed/NCBI