Attenuation of bleomycin-induced pneumopathy in mice by monoclonal antibody to interleukin-12.
We previously demonstrated essential roles of the Fas-Fas ligand (FasL) pathway in bleomycin-induced pneumopathy in mice. T lymphocytes and natural killer cells express FasL on activation and use it as a cytotoxic effector molecule. Because interleukin (IL)-12 is known to play a critical role in cell-mediated immunity, we investigated whether anti-IL-12 antibody treatment suppresses the development of this model. The anti-IL-12 antibody treatment decreased the number of apoptotic cells and the degree of inflammation and fibrosis in lung tissue. The results of RT-PCR showed that IL-12p40, IL-12 receptor (R) beta2, interferon-gamma, tumor necrosis factor-alpha and FasL mRNAs were upregulated after bleomycin instillation. The upregulation of FasL, IL-12Rbeta2, and tumor necrosis factor-alpha mRNA expression in lung tissue was suppressed by anti-IL-12 antibody treatment. The results of enzyme-linked immunosorbent assay showed that the levels of IL-12p40, but not of IL-12p70, were increased in lung tissue after bleomycin instillation. Although the increase in IL-12Rbeta2 mRNA levels suggests that the T helper type 1 cell response may participate in lung injury, the increase in IL-12p40 supports T helper type 2 cell predominance in the fibrotic process of this model. The administration of anti-IL-12 antibody could be a novel therapy against lung injury and pulmonary fibrosis.
Maeyama
T
T
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Higashiku, Fukuoka 812-8582, Japan.
Kuwano
K
K
Kawasaki
M
M
Kunitake
R
R
Hagimoto
N
N
Hara
N
N
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001761:Bleomycin; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002452:Cell Count; D016207:Cytokines / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D053222:Fas Ligand Protein; D006909:Hydroxyproline / Q000378:metabolism; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
D000911:Antibodies, Monoclonal; D016207:Cytokines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D019014:fas Receptor; D001761:Bleomycin; D018664:Interleukin-12; D006909:Hydroxyproline