Abstract: Psoriasis vulgaris is a common chronic inflammatory skin disease characterized by hyperproliferative epidermis and mixed cutaneous lymphocytic infiltrate. While initially regarded as a primary disease of keratinocyte differentiation, effective immune-modulating therapies demonstrate the vital role played by the immune system in psoriatic disease pathogenesis.1–4 The T cells involved in lesion formation were initially thought to be Th1 differentiated based on interferon (IFN)-γ and interleukin (IL)-2 production.5–7 However, the recent discovery of the Th17 T-helper cell subset, and its potential involvement in psoriasis, generates even more complexity to this disease.
Th17 cells have recently been classified as distinct from Th1 and Th2 subsets.8,9 They are defined by the ability to synthesize IL-17 in response to antigen-presenting cell-derived IL-23 and other differentiating cytokines.10–13 In addition, Th17 cells have been reported to cosynthesize IL-17 and IFN-γ14 as well as IL-22.15,16 Indeed, in murine systems, IL-22 production occurs overwhelmingly within the Th17 subset.15
Psoriatic skin lesions are reported to have increased gene expression of IL-23,17 IL-17 and IL-22,18–21 prompting investigators to probe deeper into the potential involvement of Th17 cells in psoriasis. While models of epidermal hyperproliferation have focused on IL-22 as being central to psoriasis pathogenesis via induction of keratinocyte proliferation and acanthosis,22–24 both IL-22 and IL-17 have been shown to induce keratinocyte gene expression of antimicrobials β-defensin 2, β-defensin 3, S100A8 and S100A9, all upregulated in psoriatic lesions.15,22,25 Besides the increased expression of antimicrobial genes, however, the contribution of IL-17 to psoriasis pathogenesis has not been thoroughly investigated. This is in contrast to IL-17 being extensively implicated in chemokine-induced neutrophil recruitment in asthma, chronic obstructive pulmonary disease and cystic fibrosis.26–28
The chemokines that are considered to be neutrophil chemoattractants belong to the ELR+ CXC subfamily, named by the presence of a Glu-Leu-Arg motif at residues 4–6.29,30 Members of this subfamily include CXCL1–8, except CXCL4.29 Indeed, IL-17 has previously been shown to induce the production of CXCL1 and CXCL8 in bronchial epithelial cells,27,28 fibroblasts31 and keratinocytes,32 and neutralizing antibodies to IL-17 or its receptor can block this induction.28,32
Even with increasing evidence for the involvement of Th17 cells in psoriasis pathogenesis, the relative effects of the Th17 cytokines IL-17 and IL-22 and the Th1 cytokine IFN-γ on the skin are unknown. In this study, we sought to identify the cytokines produced by skin-resident T cells in normal skin, localize the receptors for these cytokines, and examine how these cytokines alter gene expression profiles of the cells bearing cognate receptors.