Integrated signals between IL-13, IL-4, and IL-5 regulate airways hyperreactivity.
In this investigation, we have examined the integrated relationship between IL-13, IL-4, and IL-5 for the development of airways hyperreactivity (AHR) in a model of asthma in BALB/c mice. Sensitization and aeroallergen challenge of both wild-type (WT) and IL-13 gene-targeted (IL-13-/-) mice induced allergic disease that was characterized by pulmonary eosinophilia and AHR to beta-methacholine. Although these responses in IL-13-/- mice were heightened compared with WT, they could be reduced to the level in nonallergic mice by the concomitant neutralization of IL-4. Mice in which both IL-4 and IL-13 were depleted displayed a marked reduction in tissue eosinophils, despite the development of a blood eosinophilia. Similar neutralization of IL-4 in WT mice only partially reduced AHR with no effect on tissue eosinophilia. In addition, neutralization of IL-5 in IL-13-/- mice, but not in WT mice, inhibited AHR, suggesting that tissue eosinophilia is linked to the mechanism underlying AHR only in the absence of IL-13. Additionally, mucus hypersecretion was attenuated in IL-13-/- mice, despite the persistence of AHR. Taken together, our data suggest both a modulatory role for IL-13 during sensitization and a proinflammatory role during aeroallergen challenge. The latter process appears redundant with respect to IL-4.
Webb
D C
DC
Division of Biochemistry and Molecular Biology, The John Curtin School of Medical Research, Australian National University, Canberra.
McKenzie
A N
AN
Koskinen
A M
AM
Yang
M
M
Mattes
J
J
Foster
P S
PS
D000276:Adjuvants, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D007106:Immune Sera / Q000494:pharmacology; D018793:Interleukin-13 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011657:Pulmonary Eosinophilia / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology*
D000276:Adjuvants, Immunologic; D016207:Cytokines; D007106:Immune Sera; D018793:Interleukin-13; D015848:Interleukin-5; D007378:Interleukins; D015847:Interleukin-4