Molecular mechanisms of cytokine and chemokine release from eosinophils activated by IL-17A, IL-17F, and IL-23: implication for Th17 lymphocytes-mediated allergic inflammation.
IL-17A and IL-17F are members of the IL-17 family that play crucial roles in allergic inflammation. Recent studies reported that IL-17A and IL-17F production from a distinct Th lymphocyte subset, Th17, was specifically induced by IL-23, which was produced by dendritic cells and macrophages in response to microbial stimuli. The IL-23-IL-17 axis might therefore provide a link between infections and allergic diseases. In the present study, we investigated the effects of IL-17A, IL-17F, and IL-23, alone or in combination, on cytokine and chemokine release from eosinophils and the underlying intracellular mechanisms. Human eosinophils were found to constitutively express receptors for IL-17A, IL-17F, and IL-23 at the protein level. IL-17A, IL-17F, and IL-23 could induce the release of chemokines GRO-alpha/CXCL1, IL-8/CXCL8, and MIP-1beta/CCL4 from eosinophils, while IL-17F and IL-23 could also increase the production of proinflammatory cytokines IL-1beta and IL-6. Synergistic effects were observed in the combined treatment of IL-17F and IL-23 on the release of proinflammatory cytokines, and the effects were dose-dependently enhanced by IL-23, but not IL-17F. Further investigations showed that IL-17A, IL-17F, and IL-23 differentially activated the ERK, p38 MAPK, and NF-kappaB pathways. Moreover, inhibition of these pathways using selective inhibitors could significantly abolish the chemokine release induced by IL-17A, IL-17F, and IL-23 and the synergistic increases on IL-1beta and IL-6 production mediated by combined treatment of IL-17F and IL-23. Taken together, our findings provide insight for the Th17 lymphocyte-mediated activation of eosinophils via differential intracellular signaling cascades in allergic inflammation.
Cheung
Phyllis F Y
PF
Department of Chemical Pathology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China.
Wong
Chun K
CK
Lam
Christopher W K
CW
D002478:Cells, Cultured; D018925:Chemokines / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D004804:Eosinophils / Q000276:immunology* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D053759:Interleukin-23 / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000276:immunology; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018925:Chemokines; D016207:Cytokines; C440021:IL17F protein, human; D020381:Interleukin-17; D053583:Interleukin-1beta; D053759:Interleukin-23; D015850:Interleukin-6; D016328:NF-kappa B; D011994:Recombinant Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases