| First Author | Johansen C | Year | 2015 |
| Journal | Proc Natl Acad Sci U S A | Volume | 112 |
| Issue | 43 | Pages | E5825-33 |
| PubMed ID | 26460049 | Mgi Jnum | J:227182 |
| Mgi Id | MGI:5699895 | Doi | 10.1073/pnas.1509971112 |
| Citation | Johansen C, et al. (2015) IkappaBzeta is a key driver in the development of psoriasis. Proc Natl Acad Sci U S A 112(43):E5825-33 |
| abstractText | Psoriasis is a common immune-mediated, chronic, inflammatory skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes and infiltration of inflammatory cells. Although TNFalpha- and IL-17A-targeting drugs have recently proven to be highly effective, the molecular mechanism underlying the pathogenesis of psoriasis remains poorly understood. We found that expression of the atypical IkappaB member IkappaB (inhibitor of NF-kappaB) zeta, a selective coactivator of particular NF-kappaB target genes, was strongly increased in skin of patients with psoriasis. Moreover, in human keratinocytes IkappaBzeta was identified as a direct transcriptional activator of TNFalpha/IL-17A-inducible psoriasis-associated proteins. Using genetically modified mice, we found that imiquimod-induced psoriasis-like skin inflammation was completely absent in IkappaBzeta-deficient mice, whereas skin inflammation was still inducible in IL-17A- and TNFalpha-deficient mice. IkappaBzeta deficiency also conferred resistance against IL-23-induced psoriasis. In addition, local abrogation of IkappaBzeta function by intradermal injection of IkappaBzeta siRNA abolished psoriasis-like skin inflammation. Taken together, we identify IkappaBzeta as a hitherto unknown key regulator of IL-17A-driven effects in psoriasis. Thus, targeting IkappaBzeta could be a future strategy for treatment of psoriasis, and other inflammatory diseases for which IL-17 antagonists are currently tested in clinical trials. |
