T helper (Th) 17 cells have recently been implicated in psoriasis pathogenesis, but mechanisms of how these cells traffic into inflamed skin are unknown. By immunostaining for interleukin (IL)-17A and IL-22, we show numerous cells present in psoriasis lesions that produce these cytokines. We next found that Th17 cytokines (IL-17A, IL-22, and tumor necrosis factor (TNF)-α) markedly increased the expression of CC chemokine ligand (CCL) 20, a CC chemokine receptor (CCR)6 ligand, in human keratinocyte monolayer and raft cultures in a dose- and time-dependent manner. Lastly, we showed in mice that subcutaneous injection with recombinant IL-17A, IL-22, or TNF-α led to the upregulation of both CCL20 and CCR6 expression in skin as well as cutaneous T-cell infiltration. Taken together, these data show that Th17 cytokines stimulate CCL20 production in vitro and in vivo, and thus provide a potential explanation of how CCR6-positive Th17 cells maintain their continual presence in psoriasis through a positive chemotactic feedback loop.

T helper (Th) 17 cells, a novel T-cell subset, have been implicated in the pathogenesis of psoriasis and other autoimmune inflammatory diseases. Interleukin (IL)-23 stimulates survival and proliferation of Th17 cells, and thus serves as a key master cytokine regulator for these diseases. In psoriasis, IL-23 is overproduced by dendritic cells and keratinocytes, and this cytokine stimulates Th17 cells within dermis to make IL-17A and IL-22. IL-22, in particular, drives keratinocyte hyperproliferation in psoriasis. Future targeting of these key cytokines is likely to lead to dramatic clinical improvement in patients with psoriasis. This review focuses on the numerous recent studies on the roles of IL-23 and Th17 cells in the pathogenesis of psoriasis.

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Quiescent epidermis anchors to laminin 5 in the basement membrane via integrin α6β4. Wounding elevates expression of laminin 5, generating leading keratinocytes (LKs) that migrate via β1 integrins. Laminin 5 was evaluated as a regulator of cell signaling, and mRNA and protein expression in LKs. An in vitro wound model was developed based on suspension and re-adhesion of quiescent human keratinocytes (HKs). DNA microarrays identified multiple mRNAs elevated 1.5 hours after suspension and re-adhesion including activation transcription factor 3 (ATF3). In vitro and in vivo, levels of ATF3 protein elevate in nuclei of LKs, but not in nuclei of the following cells, 2 hours after suspension or wounding but decline by 12-18 hours post injury. Significantly, null defects in laminin 5 or integrin β4 that inhibit anchorage chronically elevate ATF3 in vivo. This suggests that adhesion to laminin 5, but not other ligands, suppresses activation. On suspension, ATF3 and other transcripts in the microarrays are elevated by phosphorylated p38 mitogen-activated protein kinase (P-p38), a stress kinase that regulates mRNA and cell motility. Inhibition of P-p38 with SB203580 prevents phosphorylation of ATF2, a transcription factor for ATF3 in LKs. Re-adhesion to laminin 5 via α6β4 dephosphorylates P-p38 and suppresses ATF3 protein relative to cells in suspension. Thus, wounding of quiescent HKs disrupts laminin 5 adhesion to activate p38, generating mRNA transcripts that define LKs. Adhesion to deposits of laminin 5 via α6β4 suppresses P-p38 and activation mRNAs including ATF3. Defects in laminin 5 and α6β4 sustain P-p38 with probable pathological effects on transcription and migration. Journal of Cell Science 3472 of polarized lamellipodium in epithelial cells through activation of Rac1 (Choma et al., 2004). This sequence of adhesion and signaling changes allows HKs to make the transition from quiescence to activation in wounds. Similarly, ligation of α3β1 in A549 adenocarcinoma cells by laminin 10/11 or laminin 5 preferentially activates the Rac-MKK-JNK/p38 stress pathway that mediates epithelial migration (Gu et al., 2001;Ono and Han, 2000;Xia and Karin, 2004). In addition to adhesion, interaction of cells with integrin ligands also regulates mRNA transcription and protein translation through activation of p38 MAPK (Balda and Matter, 2003). Ligation of α6β4 activates the Rac-PAK-MKK-p38 pathway to promote expression of IL-6 in thymic epithelial cells (Mainiero et al., 2003). Thus, cell suspension and re-adhesion onto dermal collagen or laminin 5 via integrins activates JNK and/or p38 by phosphorylation to alter protein expression and/or cell motility (Clark et al., 2003;Ono and Han, 2000). Here, we sought to: (1) identify changes in mRNA transcription and protein translation in quiescent keratinocytes as they transition into wound LKs; (2) identify cell signals necessary for the transcriptional changes in LKs; (3) understand the role of laminin 5 adhesion in regulating the signaling and transcriptional changes. We found that sus...