title: Activation of discoidin domain receptor 1 isoform b with collagen up-regulates chemokine production in human macrophages: role of p38 mitogen-activated protein kinase and NF-kappa B.
abstract: Macrophages produce an array of proinflammatory mediators at sites of inflammation and contribute to the development of inflammatory responses. Important roles for cytokines, such as IL-1 or TNF-alpha, and bacterial products, such as LPS, in this process have been well documented; however, the role for the extracellular matrix proteins, such as collagen, remains unclear. We previously reported that discoidin domain receptor 1 (DDR1), a nonintegrin collagen receptor, is expressed during differentiation of human monocytes into macrophages, and the interaction of the DDR1b isoform with collagen facilitates their differentiation via the p38 mitogen-activated protein kinase (MAPK) pathway. In this study, we report that the interaction of DDR1b with collagen up-regulates the production of IL-8, macrophage inflammatory protein-1alpha, and monocyte chemoattractant protein-1 in human macrophages in a p38 MAPK- and NF-kappaB-dependent manner. p38 MAPK was critical for DDR1b-mediated, increased NF-kappaB trans-activity, but not for IkappaB degradation or NF-kappaB nuclear translocation, suggesting a role for p38 MAPK in the modification of NF-kappaB. DDR1b-mediated IkappaB degradation was mediated through the recruitment of the adaptor protein Shc to the LXNPXY motif of the receptor and the downstream TNFR-associated factor 6/NF-kappaB activator 1 signaling cascade. Taken together, our study has identified NF-kappaB as a novel target of DDR1b signaling and provided a novel mechanism by which tissue-infiltrating macrophages produce large amounts of chemokines during the development of inflammatory diseases. Intervention of DDR1b signaling may be useful to control inflammatory diseases in which these proteins play an important role.
authors.affiliation: Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick, MD 21702, USA.
authors.forename: Wataru
authors.initials: W
authors.lastname: Matsuyama
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.forename: William L
authors.initials: WL
authors.lastname: Farrar
authors.forename: Michel
authors.initials: M
authors.lastname: Faure
authors.forename: Teizo
authors.initials: T
authors.lastname: Yoshimura
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology; D002417:Cattle; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000096:biosynthesis; D054407:Chemokine CCL4; D018925:Chemokines / Q000096:biosynthesis*; D024042:Collagen Type I / Q000502:physiology*; D000070818:Discoidin Domain Receptors; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007375:Interleukin-1 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D016328:NF-kappa B / Q000096:biosynthesis / Q000502:physiology*; D020033:Protein Isoforms / Q000378:metabolism / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D011506:Proteins / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism* / Q000502:physiology; D011975:Receptors, Mitogen / Q000378:metabolism* / Q000502:physiology; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D048029:TNF Receptor-Associated Factor 6; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015534:Trans-Activators / Q000096:biosynthesis / Q000502:physiology; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D015854:Up-Regulation / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases; D018909:src Homology Domains / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D018925:Chemokines; D024042:Collagen Type I; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016209:Interleukin-8; D019402:Macrophage Inflammatory Proteins; D016328:NF-kappa B; D020033:Protein Isoforms; D011506:Proteins; D011975:Receptors, Mitogen; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D048029:TNF Receptor-Associated Factor 6; C414202:TRAF3IP2 protein, human; D015534:Trans-Activators; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate