α(1)-Acid glycoprotein up-regulates CD163 via TLR4/CD14 protein pathway: possible protection against hemolysis-induced oxidative stress.

Abstract

CD163, a scavenger receptor that is expressed at high levels in the monocyte-macrophage system, is a critical factor for the efficient extracellular hemoglobin (Hb) clearance during hemolysis. Because of the enormous detrimental effect of liberated Hb on our body by its ability to induce pro-inflammatory signals and tissue damage, an understanding of the molecular mechanisms associated with CD163 expression during the acute phase response is a central issue. We report here that α(1)-acid glycoprotein (AGP), an acute phase protein, the serum concentration of which is elevated under various inflammatory conditions, including hemolysis, up-regulates CD163 expression in both macrophage-like differentiated THP-1 (dTHP-1) cells and peripheral blood mononuclear cells in a time- and concentration-dependent manner. Moreover, the subsequent induction of Hb uptake was also observed in AGP-treated dTHP-1 cells. Among representative acute phase proteins such as AGP, α(1)-antitrypsin, C-reactive protein, and haptoglobin, only AGP increased CD163 expression, suggesting that AGP plays a specific role in the regulation of CD163. Consistently, the physiological concentrations of AGP induced CD163, and the subsequent induction of Hb uptake as well as the reduction of oxidative stress in plasma were observed in phenylhydrazine-induced hemolytic model mice, confirming the in vivo role of AGP. Finally, AGP signaling through the toll-like receptor-4 (TLR4) and CD14, the common innate immune receptor complex that normally recognizes bacterial components, was identified as a crucial stimulus that induces the autocrine regulatory loops of IL-6 and/or IL-10 via NF-κB, p38, and JNK pathways, which leads to an enhancement in CD163 expression. These findings provide possible insights into how AGP exerts anti-inflammatory properties against hemolysis-induced oxidative stress.

• Authors: Hisakazu Komori, Hiroshi Watanabe, Tsuyoshi Shuto, Azusa Kodama, Hitoshi Maeda, Kenji Watanabe, Hirofumi Kai, Masaki Otagiri, Toru Maruyama
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 36 Pg. 30688-700 (Aug 31 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 22807450 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• Antigens, Differentiation, Myelomonocytic
• CD163 antigen
• Haptoglobins
• Hemoglobins
• IL10 protein, human
• IL6 protein, human
• Interleukin-6
• Lipopolysaccharide Receptors
• NF-kappa B
• Orosomucoid
• Receptors, Cell Surface
• TLR4 protein, human
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Interleukin-10
• C-Reactive Protein
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4

Topics

• Animals
• Antigens, CD (biosynthesis)
• Antigens, Differentiation, Myelomonocytic (biosynthesis)
• C-Reactive Protein (metabolism)
• Cell Line, Tumor
• Disease Models, Animal
• Haptoglobins (metabolism)
• Hemoglobins (metabolism)
• Hemolysis
• Humans
• Interleukin-10 (metabolism)
• Interleukin-6 (metabolism)
• Lipopolysaccharide Receptors (metabolism)
• MAP Kinase Kinase 4 (metabolism)
• MAP Kinase Signaling System
• Macrophages (metabolism)
• Mice
• NF-kappa B (metabolism)
• Orosomucoid (metabolism)
• Oxidative Stress
• Receptors, Cell Surface (biosynthesis)
• Toll-Like Receptor 4 (metabolism)
• Up-Regulation
• p38 Mitogen-Activated Protein Kinases (metabolism)