Redox Modulation of HMGB1-Related Signaling

Christina Janko

Milos Filipović

Luis Munoz

Christine Schorn

Georg Schett

Ivana Ivanović-Burmazović

Martin Herrmann

^{Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.}

^{Department of Chemistry and Pharmacy, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.}

^{Corresponding author.}

Address correspondence to:, Prof. Martin Herrmann, Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University of Erlangen-Nuremberg, Ulmenweg 18, 91054 Erlangen, Germany,
E-mail:Email: ed.negnalre-ku@nnamrreh.nitram

Received 2013 Jan 18; Accepted 2013 Feb 1.

Abstract

Significance: In the cells' nuclei, high-mobility group box protein 1 (HMGB1) is a nonhistone chromatin-binding protein involved in the regulation of transcription. Extracellularly, HMGB1 acts as a danger molecule with properties of a proinflammatory cytokine. It can be actively secreted from myeloid cells or passively leak from any type of injured, necrotic cell. Increased serum levels of active HMGB1 are often found in pathogenic inflammatory conditions and correlate with worse prognoses in cancer, sepsis, and autoimmunity. By damaging cells, superoxide and peroxynitrite promote leakage of HMGB1. Recent Advances: The activity of HMGB1 strongly depends on its redox state: Inflammatory-active HMGB1 requires an intramolecular disulfide bond (Cys23 and Cys45) and a reduced Cys106. Oxidation of the latter blocks its stimulatory activity and promotes immune tolerance. Critical Issues: Reactive oxygen and nitrogen species create an oxidative environment and can be detoxified by superoxide dismutase (SOD), catalase, and peroxidases. Modifications of the oxidative environment influence HMGB1 activity. Future Directions: In this review, we hypothesize that manipulations of an oxidative environment by SOD mimics or by hydrogen sulfide are prone to decrease tissue damage. Both the concomitant decreased HMGB1 release and its redox chemical modifications ameliorate inflammation and tissue damage. Antioxid. Redox Signal. 20, 1075–1085.

Abstract

Abbreviations Used

ABC	ATP-binding cassette
Cys	cysteine
DAMP	death-associated molecular pattern
H₂S	hydrogen sulfide
HMGB1	high-mobility group box protein 1
iNOS	inducible nitric oxide synthase
LPS	lipopolysaccharide
NADPH oxidase	nicotinamide adenine dinucleotide phosphate oxidase
NF	nuclear factor
NO	nitric oxide
PARP-1	poly[ADP-ribose] polymerase 1
RAGE	receptor for advanced glycation end products
RNS	reactive nitrogen species
ROS	reactive oxygen species
SLE	systemic lupus erythematosus
SOD	superoxide dismutase
TLR	Toll-like receptor

Abbreviations Used

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