Lack of Evidence for Activation of the Hedgehog Pathway in Psoriasis

Overview

Journal J Invest Dermatol

Publisher Elsevier

Specialty Dermatology

Date 2008 Aug 30

PMID 18754037

Citations 10

Authors

Johann E Gudjonsson

Abhishek Aphale

Marina Grachtchouk

Jun Ding

Rajan P Nair

Timothy Wang

John J Voorhees

Andrzej A Dlugosz

James T Elder

Affiliations

Soon will be listed here.

Abstract

Recent reports have suggested that the hedgehog (Hh) pathway is activated in lesional psoriatic skin, and that treatment with the Hh pathway antagonist cyclopamine may lead to rapid resolution of the disease. To assess Hh pathway activity in psoriasis, we isolated RNA from lesional and uninvolved skin of 58 psoriatic patients, and from 63 normal control subjects, and subjected these samples to global gene expression profiling on Affymetrix HU133 Plus 2.0 gene arrays. We were especially interested in Hh target genes (PTCH1 and GLI1), whose expression is elevated in response to Hh signaling. The microarray data demonstrated downregulation of PTCH1 expression in uninvolved and lesional skin (1.1-fold and 2-fold, respectively; P<0.0001). Additionally GLI1 mRNA was downregulated in lesional skin (1.7 fold; P<0.05). No significant changes were observed between lesional and uninvolved skin for the Hh ligands or Smoothened. Quantitative PCR confirmed these findings. In situ hybridization for GLI1 and PTCH1 was positive in basal cell carcinoma tumor cells, but was negligible in uninvolved or lesional psoriatic skin. The absence of elevated Hh target gene expression in lesional psoriatic skin indicates that the Hh pathway is not activated in this disease, raising questions regarding the proposed use of Hh antagonists as antipsoriatic agents.

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References

Daya-Grosjean L, Couve-Privat S . Sonic hedgehog signaling in basal cell carcinomas. Cancer Lett. 2005; 225(2):181-92. DOI: 10.1016/j.canlet.2004.10.003. View

Fan H, Khavari P . Sonic hedgehog opposes epithelial cell cycle arrest. J Cell Biol. 1999; 147(1):71-6. PMC: 2164980. DOI: 10.1083/jcb.147.1.71. View

Mullor J, Sanchez P, Ruiz i Altaba A . Pathways and consequences: Hedgehog signaling in human disease. Trends Cell Biol. 2002; 12(12):562-9. DOI: 10.1016/s0962-8924(02)02405-4. View

Johansen C, Flindt E, Kragballe K, Henningsen J, Westergaard M, Kristiansen K . Inverse regulation of the nuclear factor-kappaB binding to the p53 and interleukin-8 kappaB response elements in lesional psoriatic skin. J Invest Dermatol. 2005; 124(6):1284-92. DOI: 10.1111/j.0022-202X.2005.23749.x. View

Bowcock A, Shannon W, DU F, Duncan J, Cao K, Aftergut K . Insights into psoriasis and other inflammatory diseases from large-scale gene expression studies. Hum Mol Genet. 2001; 10(17):1793-805. DOI: 10.1093/hmg/10.17.1793. View

Ruiz i Altaba A, Mas C, Stecca B . The Gli code: an information nexus regulating cell fate, stemness and cancer. Trends Cell Biol. 2007; 17(9):438-47. PMC: 2601665. DOI: 10.1016/j.tcb.2007.06.007. View

Lowrey J, Stewart G, Lindey S, Hoyne G, Dallman M, Howie S . Sonic hedgehog promotes cell cycle progression in activated peripheral CD4(+) T lymphocytes. J Immunol. 2002; 169(4):1869-75. DOI: 10.4049/jimmunol.169.4.1869. View

Lizzul P, Aphale A, Malaviya R, Sun Y, Masud S, Dombrovskiy V . Differential expression of phosphorylated NF-kappaB/RelA in normal and psoriatic epidermis and downregulation of NF-kappaB in response to treatment with etanercept. J Invest Dermatol. 2005; 124(6):1275-83. DOI: 10.1111/j.0022-202X.2005.23735.x. View

McMahon A, Ingham P, Tabin C . Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol. 2003; 53:1-114. DOI: 10.1016/s0070-2153(03)53002-2. View

10.

Johansen C, Kragballe K, Rasmussen M, Dam T, Iversen L . Activator protein 1 DNA binding activity is decreased in lesional psoriatic skin compared with nonlesional psoriatic skin. Br J Dermatol. 2004; 151(3):600-7. DOI: 10.1111/j.1365-2133.2004.06088.x. View

11.

Cooper M, Porter J, Young K, Beachy P . Teratogen-mediated inhibition of target tissue response to Shh signaling. Science. 1998; 280(5369):1603-7. DOI: 10.1126/science.280.5369.1603. View

12.

Gudjonsson J, Johnston A, Sigmundsdottir H, Valdimarsson H . Immunopathogenic mechanisms in psoriasis. Clin Exp Immunol. 2003; 135(1):1-8. PMC: 1808928. DOI: 10.1111/j.1365-2249.2004.02310.x. View

13.

Incardona J, Gaffield W, Lange Y, Cooney A, Pentchev P, Liu S . Cyclopamine inhibition of Sonic hedgehog signal transduction is not mediated through effects on cholesterol transport. Dev Biol. 2000; 224(2):440-52. DOI: 10.1006/dbio.2000.9775. View

14.

Stewart G, Lowrey J, Wakelin S, Fitch P, Lindey S, Dallman M . Sonic hedgehog signaling modulates activation of and cytokine production by human peripheral CD4+ T cells. J Immunol. 2002; 169(10):5451-7. DOI: 10.4049/jimmunol.169.10.5451. View

15.

Taipale J, Chen J, Cooper M, Wang B, MANN R, Milenkovic L . Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature. 2000; 406(6799):1005-9. DOI: 10.1038/35023008. View

16.

Johansen C, Kragballe K, Westergaard M, Henningsen J, Kristiansen K, Iversen L . The mitogen-activated protein kinases p38 and ERK1/2 are increased in lesional psoriatic skin. Br J Dermatol. 2005; 152(1):37-42. DOI: 10.1111/j.1365-2133.2004.06304.x. View

17.

McFerren M . Useful plants of dermatology. VIII. The false hellebore (Veratrum californicum). J Am Acad Dermatol. 2006; 54(4):718-20. DOI: 10.1016/j.jaad.2005.11.1075. View

18.

Ingham P, Placzek M . Orchestrating ontogenesis: variations on a theme by sonic hedgehog. Nat Rev Genet. 2006; 7(11):841-50. DOI: 10.1038/nrg1969. View

19.

Chen J, Taipale J, Cooper M, Beachy P . Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 2002; 16(21):2743-8. PMC: 187469. DOI: 10.1101/gad.1025302. View

20.

Irizarry R, Bolstad B, Collin F, Cope L, Hobbs B, Speed T . Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res. 2003; 31(4):e15. PMC: 150247. DOI: 10.1093/nar/gng015. View