Involvement of discoidin domain receptor 1 in the deterioration of pulmonary sarcoidosis.
The prognosis of sarcoidosis with pulmonary infiltrates differs in each case, and several cytokines are reported to contribute to its deterioration. However, the detailed mechanism has not been fully elucidated. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by collagen and associated with cytokine production from inflammatory cells. We previously reported the functional expression of DDR1 on CD14-positive bronchoalveolar lavage fluid (BALF) cells in vivo. In this study, we hypothesized that DDR1 might be associated with the deterioration of pulmonary sarcoidosis (PS), and investigated 33 patients with sarcoidosis with pulmonary infiltrates, prospectively. We found that patients with deteriorated PS showed significantly higher DDR1 expression in CD14-positive BALF cells predominant with DDR1b isoforms. Activation of DDR1 induced monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9) production in a p38 mitogen-activated protein kinase-dependent manner from CD14-positive BALF cells of patients with deteriorated sarcoidosis. DDR1 activation also induced NF-kappaB nuclear translocation in CD14-positive BALF cells of patients with deteriorated PS. The inhibitor of NF-kappaB inhibited the production of MCP-1 and MMP-9. We propose that DDR1 is associated with the deterioration of pulmonary sarcoidosis.
Matsuyama
Wataru
W
Division of Respiratory Medicine, Respiratory and Stress Care Center, Kagoshima University Hospital, Sakuragaoka 8-35-1, Kagoshima 890-8520, Japan. vega@xa2.so-net.ne.jp
Mitsuyama
Hideo
H
Watanabe
Masaki
M
Shirahama
Yuko
Y
Higashimoto
Ikkou
I
Osame
Mitsuhiro
M
Arimura
Kimiyoshi
K
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D000070818:Discoidin Domain Receptors; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011446:Prospective Studies; D020033:Protein Isoforms; D021381:Protein Transport; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000819:agonists / Q000276:immunology / Q000378:metabolism*; D017565:Sarcoidosis, Pulmonary / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018932:Chemokine CCL2; D018950:Lipopolysaccharide Receptors; D016328:NF-kappa B; D020033:Protein Isoforms; D011975:Receptors, Mitogen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9