Soluble ICAM-1 activates lung macrophages and enhances lung injury.
Because of the important role of rat ICAM-1 in the development of lung inflammatory injury, soluble recombinant rat ICAM-1 (sICAM-1) was expressed in bacteria, and its biologic activities were evaluated. Purified sICAM-1 did bind to rat alveolar macrophages in a dose-dependent manner and induced production of TNF-alpha and the CXC chemokine, macrophage inflammatory protein-2 (MIP-2). Alveolar macrophages exhibited cytokine responses to both sICAM-1 and immobilized sICAM-1, while rat PBMCs failed to demonstrate similar responses. Exposure of alveolar macrophages to sICAM-1 resulted in NFkappaB activation (which was blocked by the presence of the aldehyde peptide inhibitor of 28S proteosome and by genistein, a tyrosine kinase inhibitor). As expected, cross-linking of CD18 on macrophages with Ab resulted in generation of TNF-alpha and MIP-2. This response was also inhibited in the presence of the proteosome inhibitor and by genistein. Alveolar macrophages showed adherence to immobilized sICAM-1 in a CD18-dependent manner. Finally, airway instillation of sICAM-1 intensified lung injury produced by intrapulmonary deposition of IgG immune complexes in a manner associated with enhanced lung production of TNF-alpha and MIP-2 and increased neutrophil recruitment. Therefore, through engagement of beta2 integrins, sICAM-1 enhances alveolar macrophage production of MIP-2 and TNF-alpha, the result of which is intensified lung injury after intrapulmonary disposition of immune complexes.
Schmal
H
H
Department of Traumatology, University of Freiburg, Germany.
Czermak
B J
BJ
Lentsch
A B
AB
Bless
N M
NM
Beck-Schimmer
B
B
Friedl
H P
HP
Ward
P A
PA
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000280:Administration, Inhalation; D000818:Animals; D015152:Blotting, Northern; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D018821:CD18 Antigens / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D002478:Cells, Cultured; D054426:Chemokine CXCL2; D018799:Intercellular Adhesion Molecule-1 / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism; D008297:Male; D015846:Monokines / Q000096:biosynthesis; D011485:Protein Binding / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D015398:Signal Transduction / Q000276:immunology; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000276:Adjuvants, Immunologic; D018821:CD18 Antigens; D054426:Chemokine CXCL2; D008024:Ligands; D015846:Monokines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1