IL-9 regulates allergen-specific Th1 responses in allergic contact dermatitis.
The cytokine IL-9, derived primarily from T-helper 9 (Th9) lymphocytes, promotes expansion of the Th2 subset and is implicated in the mechanisms of allergic asthma. We hypothesize that IL-9 also has a role in human allergic contact dermatitis (ACD). To investigate this hypothesis, skin biopsy specimens of positive patch-test sites from non-atopic patients were assayed using quantitative PCR and immunohistochemistry. The cytokines IFN-γ, IL-4, IL-17A, IL-9, and PU.1, a Th9 associated transcription factor, were elevated when compared with paired normal skin. Immunohistochemistry on ACD skin biopsies identified PU.1+ CD3+ and PU.1+ CD4+ cells, consistent with Th9 lymphocytes, in the inflammatory infiltrate. Peripheral blood mononuclear cells from nickel-allergic patients, but not nonallergic controls, show significant IL-9 production in response to nickel. Blocking studies with mAbs to HLA-DR (but not HLA-A, -B, -C) or chloroquine significantly reduced this nickel-specific IL-9 production. In addition, blockade of IL-9 or IL-4 enhanced allergen-specific IFN-γ production. A contact hypersensitivity model using IL-9(-/-) mice shows enhanced Th1 lymphocyte immune responses, when compared with wild-type mice, consistent with our human in vitro data. This study demonstrates that IL-9, through its direct effects on Th1 and ability to promote IL-4 secretion, has a regulatory role for Th1 lymphocytes in ACD.
Department of Dermatology, University of Maryland, Baltimore, Maryland, USA.
Juan
J
Liu
Department of Dermatology, University of Maryland, Baltimore, Maryland, USA; Department of Microbiology/Immunology, University of Maryland, Baltimore, Maryland, USA.
Erin
E
Harberts
Department of Dermatology, University of Maryland, Baltimore, Maryland, USA; Department of Dermatology, La Sapienza University, Rome, Italy.
Antonella
A
Tammaro
Drexel University, Philadelphia, Pennsylvania, USA.
Nicholas
N
Girardi
Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA.
Renata B
RB
Filler
Department of Dermatology, University of Maryland, Baltimore, Maryland, USA.
Rita
R
Fishelevich
Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
Angela
A
Temann
Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
Paula
P
Licona-Limón
Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA.
Michael
M
Girardi
Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
Richard A
RA
Flavell
Department of Dermatology, University of Maryland, Baltimore, Maryland, USA; Department of Microbiology/Immunology, University of Maryland, Baltimore, Maryland, USA. Electronic address: agasp001@umaryland.edu.
Anthony A
AA
Gaspari
D000328:Adult; D000368:Aged; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D017449:Dermatitis, Allergic Contact / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D016906:Interleukin-9 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009532:Nickel / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
D015847:Interleukin-4; D016906:Interleukin-9; D009532:Nickel; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C508598:IL4 protein, human; C508607:IL9 protein, human