Hepcidin induction by pathogens and pathogen-derived molecules is strongly dependent on interleukin-6

Area of Science:

• Immunology
• Endocrinology
• Molecular Biology

Background:

• Hepcidin, an iron-regulatory hormone, increases during infection and inflammation, leading to hypoferremia.
• This response is believed to be a host defense mechanism limiting iron for pathogens.
• The specific regulation of hepcidin by different infection types and signaling pathways remains unclear.

Purpose of the Study:

• To investigate hepcidin induction by bacterial and viral infections.
• To determine the role of interleukin-6 (IL-6) in hepcidin regulation during infection.
• To examine the direct regulation of hepcidin transcription by pattern recognition receptors.

Main Methods:

• Analysis of hepcidin induction in wild-type and IL-6 knockout mice during bacterial (Streptococcus pneumoniae) and viral (influenza) infections.
• Treatment of mice and human primary hepatocytes with pathogen-associated molecular patterns (PAMPs) and Toll-like receptor ligands.
• Assessment of hepcidin mRNA levels and the effect of IL-6 neutralization.

Main Results:

• Both bacterial and viral infections significantly induced hepcidin mRNA in wild-type mice.
• Toll-like receptor ligand stimulation rapidly increased hepcidin mRNA in mice and human hepatocytes.
• Hepcidin induction by microbial stimuli was dependent on IL-6, as evidenced by studies in IL-6 knockout mice and in vitro experiments with IL-6 neutralizing antibodies.

Conclusions:

• Interleukin-6 (IL-6) plays a pivotal role in hepcidin regulation in response to diverse infectious and inflammatory stimuli.
• The findings highlight IL-6 as a key mediator of the hypoferremic response during infection.
• This study clarifies the signaling pathway involving IL-6 in infection-induced hepcidin regulation.