Redox Rep 2001;6(6):379-85
Haptoglobin, an inflammation-inducible plasma protein.
Wang Y, Kinzie E, Berger FG, Lim SK, Baumann H.
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Sterile tissue injury or infection initiates a local inflammatory response
that mobilizes a systemic acute phase reaction resulting in, among other
things, the induction of genes encoding the acute phase plasma proteins
(APPs). In all vertebrates, a common set of APPs is increased and exerts
essential protective functions. Haptoglobin (HP), one of the major APPs,
acts as a high-affinity
hemoglobin-binding protein and antioxidant. Liver is the major site
of HP synthesis; however, regulated, low level expression is also detected
in other organs. Induction of the Hp gene is mediated by interleukin-6-type
cytokines and is synergistically enhanced by glucocorticoids. Growth stimulation
of hepatic cells in vivo or in vitro suppresses the Hp gene-inducing effects
of inflammatory cytokines. Receptors for IL-6 cytokines mediate induction
of the Hp gene by the transcription factors signal transducer and activator
of transcription-3 (STAT3) and CAAT/enhancer binding protein beta (C/EBPbeta),
but attenuate the stimulation through co-activated STAT5 and mitogen-activated
protein kinases, ERK-1 and ERK-2. The specificity by which the related
cytokines, IL-6, oncostatin M, and leukemia inhibitory factor, regulate
Hp gene transcription is determined by the profile of the cytokine receptor
subunits expressed on the target cells and the relative extents by which
these receptors activate the intracellular signaling pathways. The current
hypothesis is that HP exerts an anti-inflammatory activity and that by
the degree with which HP attenuates the inflammatory process, including
the production of IL-6 cytokines, it determines the level and duration
of acute phase expression of the Hp gene.