The Journal of Experimental Medicine
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Published online October 1, 2007
doi:10.1084/jem.20070157
The Journal of Experimental Medicine, Vol. 204, No. 11, 2603-2614
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Blumberg et al.
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ARTICLE

 Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation

Hal Blumberg1, Huyen Dinh1, Esther S. Trueblood2, James Pretorius4, David Kugler1, Ning Weng3, Suzanne T. Kanaly2, Jennifer E. Towne1, Cynthia R. Willis1, Melanie K. Kuechle5, John E. Sims1, and Jacques J. Peschon1

1 Department of Inflammation, 2 Department of Pathology, 3 Department of Biostatistics, Amgen, Seattle, WA 98119
4 Department of Pathology, Amgen, Thousand Oaks, CA 91320
5 Department of Dermatology, University of Washington School of Medicine, Seattle, WA 98105

CORRESPONDENCE Hal Blumberg: blumberh{at}amgen.com

The interleukin (IL)-1 family members IL-1{alpha}, -1ß, and -18 are potent inflammatory cytokines whose activities are dependent on heterodimeric receptors of the IL-1R superfamily, and which are regulated by soluble antagonists. Recently, several new IL-1 family members have been identified. To determine the role of one of these family members in the skin, transgenic mice expressing IL1F6 in basal keratinocytes were generated. IL1F6 transgenic mice exhibit skin abnormalities that are dependent on IL-1Rrp2 and IL-1RAcP, which are two members of the IL-1R family. The skin phenotype is characterized by acanthosis, hyperkeratosis, the presence of a mixed inflammatory cell infiltrate, and increased cytokine and chemokine expression. Strikingly, the combination of the IL-1F6 transgene with an IL1F5 deficiency results in exacerbation of the skin phenotype, demonstrating that IL-1F5 has antagonistic activity in vivo. Skin from IL1F6 transgenic, IL1F5–/– pups contains intracorneal and intraepithelial pustules, nucleated corneocytes, and dilated superficial dermal blood vessels. Additionally, expression of IL1RL2, -1F5, and -1F6 is increased in human psoriatic skin. In summary, dysregulated expression of novel agonistic and antagonistic IL-1 family member ligands can promote cutaneous inflammation, revealing potential novel targets for the treatment of inflammatory skin disorders.

Abbreviations used: AcP, accessory protein; bp, binding protein; HE, hematoxylin and eosin; IHC, immunohistochemistry; ICAM, intercellular adhesion molecule; ISH, in situ hybridization; MAP, multiple analyte panel; P, postnatal day.

S.T. Kanaly's present address is Dept. of Pathology, Allergan, Inc., Irvine, CA 92612.

J.J. Peschon's present address is Institute for Systems Biology, Seattle, WA 98103.


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