Discoidin domain receptor 1 mediates collagen-induced nitric oxide production in J774A.1 murine macrophages.
Nitric oxide (NO) is an important regulator of immune responses. Effects of cytokines, such as tumor necrosis factor (TNF)-alpha or IFN-gamma, and bacterial products, such as lipopolysaccharide, on macrophage NO production have been well documented; however, the role of the extracellular matrix proteins, including collagen, in this process remains unclear. We previously reported that discoidin domain receptor 1 (DDR1), a nonintegrin collagen receptor, was expressed in human macrophages, and its activation facilitated their differentiation as well as cytokine/chemokine production. Here, we examined the role for DDR1 in collagen-induced NO production using the murine macrophage cell line J774 cells that endogenously express DDR1. Activation of J774 cells with collagen induced the expression of inducible NO synthase (iNOS) and NO production. Inhibition of DDR1, but not beta1-integrins, abolished collagen-induced iNOS and NO production. Activation of J774 cells with collagen-activated nuclear factor-kappaB, p38 mitogen-activated protein kinase (MAPK), and c-jun N-terminal kinase (JNK) and a pharmacological inhibitor of each signaling molecule significantly reduced collagen-induced NO production. Thus, we have demonstrated, for the first time, that the interaction of DDR1 with collagen induces iNOS expression and subsequent NO synthesis in J774 cells through activation of NF-kappaB, p38 MAPK, and JNK and suggest that intervention of DDR1 signaling in macrophages may be useful in controlling inflammatory diseases in which NO plays a critical role.
Kim
Sang-Hyun
SH
Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422, Korea. shkim72@knu.ac.kr
Lee
Soyoung
S
Suk
Kyoungho
K
Bark
Hyun
H
Jun
Chang-Duk
CD
Kim
Dae-Ki
DK
Choi
Cheol-Hee
CH
Yoshimura
Teizo
T
D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology / Q000502:physiology*; D000070819:Discoidin Domain Receptor 1; D004789:Enzyme Activation; D004790:Enzyme Induction; D019012:Integrin beta1 / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D019012:Integrin beta1; D008565:Membrane Proteins; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D009569:Nitric Oxide; D003094:Collagen; D052247:Nitric Oxide Synthase Type II; C083249:Ddr1 protein, mouse; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4