Signal transducer and activator of transcription 3 (STAT3), a protein involved in transmitting extracellular signals to the nucleus, is crucial to the development of the skin disease psoriasis, according to a study published in the January issue of Nature Medicine. Psoriasis is a common inflammatory skin disorder; however, whether its pathogenesis results from abnormal skin cells, keratinocytes or autoimmune responses has remained unclear, until now.

STAT proteins transmit signals from cytokines or growth factors that have cell-surface receptors associated with tyrosine kinase activity. Kinases, such as members of the Janus kinase family or SRC family, phosphorylate these receptors and provide docking sites for inactive STAT monomers, which are in turn phosphorylated and form activated dimers. Activated STATS move to the nucleus and are involved in regulating many genes that control fundamental biological process including apoptosis, cell proliferation and immune responses.

John DiGiovanni and colleagues report that keratinocytes in psoriatic lesions express STAT3. The authors generated a mouse model in which keratinocytes express large amounts of constitutively active STAT3. Within 2 weeks of birth, these mice developed a skin phenotype that closely resembles human psoriasis. Histological, immunochemical and gene-expression analyses revealed many features of psoriasis, including epidermal hyperplasia, increased keratinocyte replication, inflammatory cell infiltration within the dermis and epidermis, and increased expression of molecules such as VEGF, ICAM-1, TGF-α, cyclin D1 and IκB-α.

Blocking the function of STAT3 using antisense oligonucleotides inhibited the onset of, and reversed, established psoriatic lesions. Further analysis revealed a dual requirement for both activated STAT3 in keratinocytes as well as in T cells, indicating that the pathogenesis of psoriasis is rooted in a co-operative process involving STAT3-regulated genes in both skin cells and the immune system.

The results of this study indicate that inhibiting the activation of STAT3 could be beneficial in the treatment of psoriasis. Interestingly, constitutive activation of STAT3 has been observed in several tumours, and antagonising its expression induces apoptosis of cancer cells and inhibits angiogenesis.