Intrinsic defect in T cell production of interleukin (IL)-13 in the absence of both IL-5 and eotaxin precludes the development of eosinophilia and airways hyperreactivity in experimental asthma.
Interleukin (IL)-5 and IL-13 are thought to play key roles in the pathogenesis of asthma. Although both cytokines use eotaxin to regulate eosinophilia, IL-13 is thought to operate a separate pathway to IL-5 to induce airways hyperreactivity (AHR) in the allergic lung. However, identification of the key pathway(s) used by IL-5 and IL-13 in the disease process is confounded by the failure of anti-IL-5 or anti-IL-13 treatments to completely inhibit the accumulation of eosinophils in lung tissue. By using mice deficient in both IL-5 and eotaxin (IL-5/eotaxin(-/-)) we have abolished tissue eosinophilia and the induction of AHR in the allergic lung. Notably, in mice deficient in IL-5/eotaxin the ability of CD4(+) T helper cell (Th)2 lymphocytes to produce IL-13, a critical regulator of airways smooth muscle constriction and obstruction, was significantly impaired. Moreover, the transfer of eosinophils to IL-5/eotaxin(-/-) mice overcame the intrinsic defect in T cell IL-13 production. Thus, factors produced by eosinophils may either directly or indirectly modulate the production of IL-13 during Th2 cell development. Our data show that IL-5 and eotaxin intrinsically modulate IL-13 production from Th2 cells and that these signaling systems are not necessarily independent effector pathways and may also be integrated to regulate aspects of allergic disease.
Mattes
Joerg
J
Division of Biochemistry and Molecular Biology, The John Curtin School of Medical Research, Australian National University, Canberra, ACT 0200, Australia.
Yang
Ming
M
Mahalingam
Surendran
S
Kuehr
Joachim
J
Webb
Dianne C
DC
Simson
Ljubov
L
Hogan
Simon P
SP
Koskinen
Aulikki
A
McKenzie
Andrew N J
AN
Dent
Lindsay A
LA
Rothenberg
Marc E
ME
Matthaei
Klaus I
KI
Young
Ian G
IG
Foster
Paul S
PS
D019264:Adoptive Transfer; D000818:Animals; D001249:Asthma / Q000150:complications* / Q000276:immunology / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000150:complications / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000150:complications / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004804:Eosinophils / Q000378:metabolism / Q000637:transplantation; D017353:Gene Deletion; D006801:Humans; D018793:Interleukin-13 / Q000096:biosynthesis / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism; D015848:Interleukin-5 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013183:Sputum / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
C515456:CCL11 protein, human; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D018793:Interleukin-13; D020382:Interleukin-18; D015848:Interleukin-5; D012333:RNA, Messenger