Protective effects of IL-4, IL-10, IL-12, and IL-13 in IgG immune complex-induced lung injury: role of endogenous IL-12.
Using the IgG immune complex (BSA-anti-BSA) model of acute lung injury in rats, we have compared four intratracheally administered cytokines for their protective effects on parameters of injury (albumin leak and hemorrhage) and on neutrophil accumulation (lung content of myeloperoxidase). The descending rank order of protective effects was: IL-10 > or = IL-13 > IL-4 > > IL-12. In animals receiving an intratracheal instillation of 1.0 microg murine rIL-4, IL-10, IL-12 or IL-13, the levels of TNF-alpha in bronchoalveolar (BAL) fluids after intrapulmonary deposition of IgG immune complexes were reduced by 98, 98, 34, and 97%, respectively, implying a corresponding reduction in up-regulation of lung vascular intercellular adhesion molecule-1. The unexpected findings with IL-12 were further evaluated. In spite of reduced BAL levels of TNF-alpha in IL-12-treated animals, BAL levels of IFN-gamma were elevated sixfold, indicative of the expected biologic response to IL-12. Alveolar macrophages obtained from the same animals showed a 68% reduction in formation in vitro of NO2-/NO3-. When rats undergoing intrapulmonary deposition of IgG immune complexes were treated either i.v. or intratracheally with blocking Ab to murine IL-12, there were significant increases in lung permeability and myeloperoxidase values, suggesting that in this model intrinsic IL-12 functions in a regulatory manner. In homogenates of injured lungs, this Ab detected heterodimeric complex, consistent with rat IL-12. These data confirm the ability of certain cytokines to suppress in vivo lung inflammatory responses and underscore the unexpected anti-inflammatory activities of IL-12.
Mulligan
M S
MS
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109, USA.
Warner
R L
RL
Foreback
J L
JL
Shanley
T P
TP
Ward
P A
PA
D000818:Animals; D000936:Antigen-Antibody Complex / Q000633:toxicity*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004195:Disease Models, Animal; D007074:Immunoglobulin G / Q000633:toxicity*; D016753:Interleukin-10 / Q000627:therapeutic use; D018664:Interleukin-12 / Q000378:metabolism / Q000502:physiology* / Q000627:therapeutic use; D018793:Interleukin-13 / Q000627:therapeutic use; D015847:Interleukin-4 / Q000627:therapeutic use; D007378:Interleukins / Q000627:therapeutic use*; D008168:Lung / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009195:Peroxidase / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D000936:Antigen-Antibody Complex; D007074:Immunoglobulin G; D018793:Interleukin-13; D007378:Interleukins; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D009195:Peroxidase