IL-17 and IL-22 enhance skin inflammation by stimulating the secretion of IL-1β by keratinocytes via the ROS-NLRP3-caspase-1 pathway.
BACKGROUND
The pathogenesis of inflammatory skin disease involves the release of cytokines from keratinocytes, and one of these, IL-1β, has been previously implicated in inflammatory skin disease. T(h)17 cells, a subset of T(h) cells involved in autoimmunity and inflammation, possess IL-1β receptors and secrete cytokines such as IL-17 and IL-22 in response to IL-1β stimulation. A mutation in the inflammasome protein NLRP3 (NACHT, LRR and PYD domains-containing protein 3) causes excess production of IL-1β, resulting in an augmentation of T(h)17-dominant pathology.


METHODS
To determine the feedback effect, if any, of IL-17 and/or IL-22 on the secretion of IL-1β from keratinocytes, we stimulated the human keratinocyte cell line HaCaT, as well as caspase-1-deficient mice, with IL-17 or IL-22.


RESULTS
We found that treatment with IL-17 and IL-22 causes an increase in IL-1β via the activation of NLRP3 by a process that involves the generation of reactive oxygen species. Moreover, skin inflammation induced by IL-17 and IL-22 was lower in caspase-1 knockout (KO) mice relative to that induced by IL-1β treatment. Additionally, skin inflammation induced by the drug imiquimod was lower in caspase-1 KO mice than in wild-type mice.


CONCLUSIONS
These results indicate that cytokines from T(h)17 cells may potentiate IL-1β-mediated skin inflammation and result in phenotypic alterations of keratinocytes via a feedback mechanism.
Department of Microbiology, School of Medicine, Ewha Womans University, Seoul, Korea.
Kyung-Ah
KA
Cho
Jee Won
JW
Suh
Kyung Ho
KH
Lee
Jihee Lee
JL
Kang
So-Youn
SY
Woo
D000818:Animals; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism; D020170:Caspase 1 / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D012867:Skin / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology; D000097043:Interleukin-22
D002352:Carrier Proteins; D020170:Caspase 1; D020381:Interleukin-17; D053583:Interleukin-1beta; D007378:Interleukins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000097043:Interleukin-22; C453881:NLRP3 protein, human