New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25.
We have biologically characterized two new members of the IL-17 cytokine family: IL-17F and IL-25. In contrast to conventional in vitro screening approaches, we have characterized the activity of these new molecules by direct in vivo analysis and have compared their function to that of other IL-17 family members. Intranasal administration of adenovirus expressing IL-17, IL-17C, or IL-17F resulted in bronchoalveolar lavage neutrophilia and inflammatory gene expression in the lung. In contrast, intranasal administration of IL-25-expressing adenovirus or IL-25 protein resulted in the production of IL-4, IL-5, IL-13, and eotaxin mRNA in the lung and marked eosinophilia in the bronchoalveolar lavage and lung tissue. Mice given intranasal IL-25 also developed epithelial cell hyperplasia, increased mucus secretion, and airway hyperreactivity. IL-25 gene expression was detected following Aspergillus and Nippostrongylus infection in the lung and gut, respectively. IL-25-induced eosinophilia required IL-5 and IL-13, but not IL-4 or T cells. Following IL-25 administration, the IL-5(+) staining cells were CD45R/B220(+), Thy-1(+/-), but were NK1.1-, Ly-6G(GR-1)-, CD4-, CD3-, and c-kit-negative. gamma-common knockout mice did not develop eosinophilia in response to IL-25, nor were IL-5(+) cells detected. These findings suggest the existence of a previously unrecognized cell population that may initiate Th2-like responses by responding to IL-25 in vivo. Further, these data demonstrate the heterogeneity of function within the IL-17 cytokine family and suggest that IL-25 may be an important mediator of allergic disease via production of IL-4, IL-5, IL-13, and eotaxin.
Hurst
Stephen D
SD
DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, CA 94304, USA. hurst@corgentech.com
Muchamuel
Tony
T
Gorman
Daniel M
DM
Gilbert
Jonathan M
JM
Clifford
Theresa
T
Kwan
Sylvia
S
Menon
Satish
S
Seymour
Brian
B
Jackson
Craig
C
Kung
Ted T
TT
Brieland
Joan K
JK
Zurawski
Sandra M
SM
Chapman
Richard W
RW
Zurawski
Gerard
G
Coffman
Robert L
RL
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000281:Administration, Intranasal; D020816:Amino Acid Motifs / Q000235:genetics / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D001228:Aspergillosis / Q000235:genetics / Q000276:immunology; D001491:Basophils / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D005260:Female; D005822:Genetic Vectors; D006098:Granulocytes / Q000276:immunology; D006133:Growth Substances / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D018793:Interleukin-13 / Q000502:physiology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015848:Interleukin-5 / Q000096:biosynthesis / Q000502:physiology; D007378:Interleukins; D007411:Intestinal Diseases, Parasitic / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D007964:Leukocytosis / Q000235:genetics / Q000276:immunology / Q000821:virology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016131:Lymphocyte Subsets / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009093:Mucus / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology / Q000821:virology; D011657:Pulmonary Eosinophilia / Q000235:genetics / Q000276:immunology / Q000821:virology; D012333:RNA, Messenger / Q000096:biosynthesis; D017386:Sequence Homology, Amino Acid; D017206:Strongylida Infections / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism*; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism*
D006133:Growth Substances; C440021:IL17F protein, human; C486701:IL25 protein, human; D018793:Interleukin-13; D020381:Interleukin-17; D015848:Interleukin-5; D007378:Interleukins; C464565:MYDGF protein, human; C442281:Mydgf protein, mouse; D012333:RNA, Messenger