An IL-17F/A heterodimer protein is produced by mouse Th17 cells and induces airway neutrophil recruitment.
IL-17A and IL-17F are related homodimeric proteins of the IL-17 family produced by Th17 cells. In this study, we show that mouse Th17 cells also produce an IL-17F/A heterodimeric protein. Whereas naive CD4(+) T cells differentiating toward the Th17 cell lineage expressed IL-17F/A in higher amounts than IL-17A/A homodimer and in lower amounts than IL-17F/F homodimer, differentiated Th17 cells expressed IL-17F/A in higher amounts than either homodimer. In vitro, IL-17F/A was more potent than IL-17F/F and less potent than IL-17A/A in regulating CXCL1 expression. Neutralization of IL-17F/A with an IL-17A-specific Ab, and not with an IL-17F-specific Ab, reduced the majority of IL-17F/A-induced CXCL1 expression. To study these cytokines in vivo, we established a Th17 cell adoptive transfer model characterized by increased neutrophilia in the airways. An IL-17A-specific Ab completely prevented Th17 cell-induced neutrophilia and CXCL5 expression, whereas Abs specific for IL-17F or IL-22, a cytokine also produced by Th17 cells, had no effects. Direct administration of mouse IL-17A/A or IL-17F/A, and not IL-17F/F or IL-22, into the airways significantly increased neutrophil and chemokine expression. Taken together, our data elucidate the regulation of IL-17F/A heterodimer expression by Th17 cells and demonstrate an in vivo function for this cytokine in airway neutrophilia.
Liang
Spencer C
SC
Inflammation Technologies, Wyeth Research, Cambridge, MA 02140, USA.
Long
Andrew J
AJ
Bennett
Frann
F
Whitters
Matthew J
MJ
Karim
Riyez
R
Collins
Mary
M
Goldman
Samuel J
SJ
Dunussi-Joannopoulos
Kyriaki
K
Williams
Cara M M
CM
Wright
Jill F
JF
Fouser
Lynette A
LA
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D019281:Dimerization; D004195:Disease Models, Animal; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000276:immunology; D008168:Lung / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D020556:Neutrophil Infiltration / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D020381:Interleukin-17