Distinct spatial requirement for eosinophil-induced airways hyperreactivity.
T helper (Th)-2-derived cytokines and their involvement in the recruitment and activation of inflammatory cells crucially orchestrate asthma pathogenesis. A notable cellular component of this allergy-induced inflammation is the eosinophil. However, whether the eosinophil is an obligatory mediator for enhancing airways hyperreactivity (AHR) to cholinergic stimuli, a watershed of the asthmatic lung, is somewhat controversial. In this investigation we have endeavoured to define the spatial requirements for IL-4 and IL-13, and the downstream effector molecules, IL-5 and the CC chemokine eotaxin, for the recruitment of eosinophils and the development of AHR in a murine model of allergic pulmonary disease. These studies are of particular importance considering clinical trials, with either the soluble IL-4Ralpha subunit or a humanized anti-IL-5 antibody, are being conducted. Interestingly, our studies show that depletion of both IL-4 and IL-13 is necessary to ablate pulmonary eosinophilia and AHR, and that this may be attributed to the role these cytokines play in regulating the expression of the eosinophil- activating molecules, IL-5 and eotaxin. While it is clear that depletion of IL-5 diminishes pulmonary eosinophilia, we demonstrate in BALB/c mice that a deficiency in both IL-5 and eotaxin is necessary to abolish both the trafficking of eosinophils to the lung and AHR. However, in contrast to the neutrophil-rich inflammation observed in mice deficient in both IL-4 and IL-13, inflammation per se in mice deficient in both IL-5 and eotaxin is significantly attenuated. This suggests that asthma immunotherapy may be better directed towards the eosinophil- activating molecules IL-5 and eotaxin, rather than towards pleiotrophic molecules such IL-4 and IL-13, which are additionally important in modulating alternative inflammatory responses.
Webb
D C
DC
Leukocyte Signalling and Regulation Laboratory, Division of Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, Australian Capital Territory, Australia.
McKenzie
A N
AN
Matthaei
K I
KI
Rothenberg
M E
ME
Foster
P S
PS
D000818:Animals; D001249:Asthma / Q000276:immunology*; D054413:Chemokine CCL11; D019742:Chemokines, CC; D016207:Cytokines / Q000276:immunology; D004804:Eosinophils / Q000276:immunology*; D006801:Humans; D018793:Interleukin-13 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D015848:Interleukin-5 / Q000276:immunology; D008168:Lung / Q000276:immunology*
C515456:CCL11 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; D016207:Cytokines; D018793:Interleukin-13; D015848:Interleukin-5; D015847:Interleukin-4