Regulation of hepcidin transcription by interleukin-1 and interleukin-6 - PubMed (original) (raw)

Regulation of hepcidin transcription by interleukin-1 and interleukin-6

Pauline Lee et al. Proc Natl Acad Sci U S A. 2005.

Abstract

Hepcidin is a peptide that regulates iron homeostasis by inhibiting iron absorption by the small intestine and release of iron from macrophages. Its production is stimulated by iron overload and by inflammation. It has been suggested that IL-6 is the only cytokine that stimulates hepcidin transcription. However, mice with targeted disruption of the gene encoding IL-6 (IL-6-/-) respond to endotoxin by increasing the expression of hepcidin transcripts in the liver. We show that incubating murine hepatocytes with IL-6, IL-1alpha, and IL-1beta strongly stimulates hepcidin transcription. IL-10 has little or no stimulatory effect, and IFN-beta inhibits transcription of hepcidin. All of the hepcidin stimulatory activity of macrophages from IL-6-/- mice can be accounted for by IL-1 that they secrete. Hepatocytes from IL-6-/- mice, hfe-/- mice, and mice with a hypomorphic transferrin receptor 2 mutation responded to IL-6 and IL-1 by up-regulating hepcidin transcription. Nitric oxide does not seem to be involved in the stimulation of hepcidin transcription by cytokines: aminoguanidine does not inhibit the stimulation of hepcidin transcription by cytokines. IL-1 may play a significant role in the anemia of inflammation by up-regulating hepcidin.

PubMed Disclaimer

Figures

Fig. 1.

Fig. 1.

The effect of IL-6, IL-1α, IL-1β, IL-10 (20 ng/ml), IFN-β (250 units/ml), and cognate antibodies against these cytokines on the expression of hepcidin by primary murine hepatocytes. The target hepatocytes were derived from CB57Bl6, IL-6–/–, _hfe_–/–, and _tfr2_-mutant mice, as indicated. Each symbol represents one experiment in which two to four samples of primary murine hepatocytes were incubated with culture medium (control) or with the cytokine and antibody combination indicated.

Fig. 2.

Fig. 2.

The effect of adding 50% conditioned medium (CM) from IL-6–/– macrophages with and without antibodies against mouse IL-6, IL-1α, and/or IL-1β to primary murine hepatocytes derived from the strains of mice indicated in the boxes. Each symbol represents one experiment in which two to four samples of primary murine hepatocytes were incubated with culture medium (control) or with the antibody combination indicated for 24 h.

Fig. 3.

Fig. 3.

The effect of aminoguanidine (AG), a nonspecific inhibitor of NOS, on hepcidin transcription in C57 BL, IL-6–/–, _hfe_–/–, and _tfr2_-mutant mice. Each bar represents the average results obtained from two to four samples of primary murine hepatocytes derived from the indicated strains of mice. Hatched bars represent hepcidin transcription in the presence of the inhibitor.

Similar articles

Cited by

References

    1. Krause, A., Neitz, S., Magert, H. J., Schulz, A., Forssmann, W. G., Schulz-Knappe, P. & Adermann, K. (2000) FEBS Lett. 480, 147–150. - PubMed
    1. Park, C. H., Valore, E. V., Waring, A. J. & Ganz, T. (2001) J. Biol. Chem. 276, 7806–7810. - PubMed
    1. Pigeon, C., Ilyin, G., Courselaud, B., Leroyer, P., Turlin, B., Brissot, P. & Loreal, O. (2001) J. Biol. Chem. 276, 7811–7819. - PubMed
    1. Nicolas, G., Bennoun, M., Devaux, I., Beaumont, C., Grandchamp, B., Kahn, A. & Vaulont, S. (2001) Proc. Natl. Acad. Sci. USA 98, 8780–8785. - PMC - PubMed
    1. Nemeth, E., Rivera, S., Gabayan, V., Keller, C., Taudorf, S., Pedersen, B. K. & Ganz, T. (2004) J. Clin. Invest. 113, 1271–1276. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources