Psoriasis is a frequent, inflammatory disease of skin and joints with considerable morbidity. Here we report that in psoriatic lesions, epidermal keratinocytes have decreased expression of JunB, a gene localized in the psoriasis susceptibility region PSORS6. Likewise, inducible epidermal deletion of JunB and its functional companion c-Jun in adult mice leads (within two weeks) to a phenotype resembling the histological and molecular hallmarks of psoriasis, including arthritic lesions. In contrast to the skin phenotype, the development of arthritic lesions requires T and B cells and signalling through tumour necrosis factor receptor 1 (TNFR1). Prior to the disease onset, two chemotactic proteins (S100A8 and S100A9) previously mapped to the psoriasis susceptibility region PSORS4, are strongly induced in mutant keratinocytes in vivo and in vitro. We propose that the abrogation of JunB/activator protein 1 (AP-1) in keratinocytes triggers chemokine/cytokine expression, which recruits neutrophils and macrophages to the epidermis thereby contributing to the phenotypic changes observed in psoriasis. Thus, these data support the hypothesis that epidermal alterations are sufficient to initiate both skin lesions and arthritis in psoriasis.
Psoriasis is a chronic disease of unsolved pathogenesis affecting skin and joints in 1–3% of the general population. It is characterized by inflamed, scaly and frequently disfiguring skin lesions and oligo-arthritis of the small joints of the hands and feet1. The skin lesions show hyperproliferation and altered differentiation of epidermal keratinocytes, marked infiltrates of T cells and neutrophils, and a distinct increase of skin capillaries1. Although at least six different psoriasis susceptibility loci, designated PSORS1–PSORS6, have been mapped by using genome-wide scans, the cause of psoriasis remains unknown2.
JunB expression is downregulated in psoriasis
Human JunB (19p13.2), a component of the AP-1 transcription factor is localized in the PSORS6 locus (19p13) and is known to regulate cell proliferation, differentiation, stress responses and cytokine expression in various organs3,4. To test a possible function of JunB/AP-1 in the aetiology of psoriasis, we analysed expression of JunB and c-Jun in unaffected and affected areas of biopsy samples (n = 8) from psoriatic patients. As recently reported for healthy human skin5, JunB was found ubiquitously expressed in all layers of the epidermis of unaffected skin of psoriatic patients with highest levels in the basal and spinous layers (Fig. 1a). Notably, the expression of JunB was greatly reduced in lesional skin of severe psoriasis (n = 6) and intermediately expressed in mild psoriasis (n = 2; data not shown), suggesting a possible role of JunB in the development of the disease. In contrast, c-Jun, which is a proposed antagonist of JunB, was (with the exception of the granular layer) only weakly expressed in normal human epidermis, but quite prominent in psoriatic skin5 (Fig. 1a). Quantification of JunB (Fig. 1b) and c-Jun expression (Fig. 1c) in different layers of the epidermis showed a strong reduction of JunB/c-Jun ratios in psoriatic skin, most prominently in the basal layer (Fig. 1d).
Inducible epidermal deletion of Jun proteins in adult mice
To study the consequence of downregulating AP-1 expression in the epidermis of adult mice, we designed inducible, conditional, single- and double-knockout mice for JunB and c-Jun. Mice carrying LoxP-site-containing (floxed) JunB and c-Jun alleles (Fig. 2a) were crossed to K5-Cre-ERT transgenic mice6, in which tamoxifen efficiently induced Cre-mediated recombination in basal layer keratinocytes. At 8 weeks of age, the single- and double-mutant mice and their littermate controls were treated with tamoxifen (Fig. 2b; 5 d, 1 mg d-1) and monitored for 18 days. Single epidermis-specific, inducible, knockout mice of JunB or c-Jun did not show any signs of a skin phenotype up to 2 months after deletion (see Supplementary Fig. 1). However, in JunB/c-Jun double-mutant mice, alterations to the hairless skin (that closely resembled the skin lesions of patients with psoriasis) appeared 8 to 10 days after tamoxifen induction. After 18 days of tamoxifen treatment, 100% of the double-mutant mice showed a strong phenotype with scaly plaques affecting primarily ears, paws and tail, and less frequently the hairy back skin (Fig. 2d–m). Histology of affected skin from mutant mice showed the hallmarks of psoriasis (Fig. 3a), such as a strongly thickened epidermis with prominent rete ridges, thickened keratinized upper layers (hyperkeratosis) with parakeratosis (nucleated keratinocytes in the cornified layer) and increased subepidermal vascularization. Intra-epidermal T cells, epidermal micro-abscesses and the typical inflammatory-cell infiltrate consisting of neutrophils were seen, along with increased numbers of macrophages in the dermis. Arthritic lesions strongly reminiscent of psoriatic arthritis (seen in 5–40% of psoriasis patients) were observed with 100% penetrance. Inflammatory infiltrates were present in the joint regions along with massive bone destruction and periostitis (Fig. 3b, c).
Molecular characterization of psoriatic phenotype
The floxed JunB and c-Jun alleles were significantly deleted in the epidermis (JunBΔep*c-JunΔep*; data not shown) and RNase protection assay for AP-1 family members demonstrated a strong reduction of c-Jun and JunB messenger RNA in the epidermis (Fig. 2c). The residual c-Jun and JunB mRNA in the epidermis (Fig. 2c) probably originates from the presence of inflammatory cells, but also from Langerhans cells and other epidermal dendritic cells (Fig. 3). A large number of cytokines, chemokines and transcription factors have been proposed to contribute to the pathogenesis of psoriasis7. Therefore, the expression of several cytokines and chemokines was analysed by an RNase protection assay (Fig. 4a). Interleukin 1α (IL-1α), IL-1β, interferon-γ (IFN-γ) and TNF-α, shown to precede other cytokines and chemokines in psoriatic lesions8, were strongly upregulated in the diseased epidermis; whereas expression of IL-18, normally induced in differentiating keratinocytes9, was found to be reduced (Fig. 4a). Macrophage inflammatory protein-2 (MIP-2; IL-8 in humans), a strong chemoattractant for neutrophils and T cells mainly produced by keratinocytes on stimulation by inflammatory cytokines7, was also strongly expressed. In addition to MIP-2, four other chemokines were found highly expressed in mutant epidermis (Fig. 4a), MIP-1α, MIP-1β, IP-10 and monocyte chemotactic protein-1 (MCP-1), which provide a strong T-cell chemotactic effect7. As described for psoriatic plaques10, upregulation of IL-12p40 was detected (Fig. 4a). In addition, reduced expression of transforming growth factor-β2 (TGF-β2), a prominent inhibitor of keratinocyte proliferation11, was seen in diseased epidermis, whereas TGF-β1 was unchanged (Fig. 4a). These results lend further support to the hypothesis that the presented mouse model largely mimics human psoriasis.
For further molecular characterization of this phenotype, global gene expression profiling was performed on two different microarrays, comprising the murine 20 k ArrayTAG (LION Bioscience; ref. 12) and the 22.4 k NIA cDNA collection from the National Institute of Ageing, combining the 15 k NIA clone set13,14 extended by 7.4 k additional sequences15 (data not shown). Analyses of genes that were deregulated at least twofold confirmed downregulation of JunB and c-Jun in diseased epidermis of mutant mice. As reported for human psoriatic keratinocytes, the chemotactic proteins S100A8 and S100A916 were upregulated at the RNA level (4.3-fold and 8.5-fold, respectively) and increased expression of S100A8 was detected by immunohistochemistry (Fig. 4b). Furthermore, epidermal fatty acid binding protein (Fabp5; 4.4-fold increase), secretory leukocyte protease inhibitor (Slpi; 3.3-fold increase), calmodulin (Calm1; 3.2-fold increase) and Gro1 (2.7-fold increase) were upregulated in diseased epidermis (data not shown). Similar to psoriasis, keratin 15 (ref. 17; 12.1-fold decrease) and caveolin18 (2.9-fold decrease) were found significantly reduced in mutant epidermis (data not shown). TIMP3 was more than sixfold downregulated in diseased epidermis of mutant mice (data not shown). It has been shown that TIMP3, besides inhibiting collagenase-1, stromelysin-1 and gelatinase A and B19 also strongly inhibits TACE20 (TNF-α-converting enzyme) thereby controlling the release of TNFα.
Induction of chemotactic S100 proteins after Jun deletion
To identify the initiating molecular events in the aetiology of psoriasis, 8-week-old double-mutant mice and their littermates were treated with tamoxifen (3 d, 1 mg d-1) and analysed 3 days after the first tamoxifen treatment. At this early time point, none of the mutant mice showed macroscopic or microscopic skin alterations (data not shown). An RNase protection assay with isolated epidermal RNA demonstrated efficient reduction of mRNA for JunB and less efficient for c-Jun, whereas other AP-1 mRNAs remained unchanged (see Supplementary Fig. 2a). None of the deregulated genes observed in the diseased mutant epidermis were significantly changed when compared to control (see Supplementary Fig. 2b–d). However, quantification of the epidermal expression of the chemotactic proteins S100A8 and S100A9, by polymerase chain reaction with reverse transcription (RT–PCR) at this early time point showed significantly increased expression in pre-diseased skin (Fig. 4c, d). To further substantiate these findings we used cultured primary keratinocytes and Cre-mediated deletion using adenovirus infection. The deletion of the Jun proteins resulted in strongly increased expression of S100A8 and S100A9 indicating negative regulation of both S100 genes (Fig. 4e). Efficient induction of S100A8 and S100A9 in cultured keratinocytes required deletion of both JunB and c-Jun (Fig. 4e), as single knockout keratinocytes showed only slightly increased levels of S100A8 and S100A9 expression. This is in agreement with the in vivo data demonstrating increased levels of S100A8 and S100A9 in double-knockout, but not in single-knockout mice, even 18 days after five tamoxifen injections (data not shown). Thus, deregulation of these proteins appears to be an early molecular event in the development of psoriasis.
Role of T cells in disease development
A functional contribution of T cells in the aetiology of psoriasis is strongly inferred from the presence of T cells in lesioned skin, but also from the induction of psoriasis-like lesions in severe combined immunodeficiency (SCID) mice transplanted with skin of psoriasis patients after transfer of autologous immune cells. The beneficial response to immunosuppressive drugs further supports this notion, however, it is still controversial whether T cells are the cause or consequence of the development of psoriasis21. To test the contribution of T cells to the development and progression of psoriasis in our genetic model, we induced deletion of JunB and c-Jun in mice deficient for Rag2 by applying the protocol shown in Fig. 2b. The skin phenotype of Rag2-deficient JunB/c-Jun double-mutant mice was milder when compared with JunB/c-Jun double-mutant mice (Fig. 5a). However, epidermal thickening, altered keratinocyte differentiation, vascular dilatation and epidermal micro-abscesses were seen, suggesting a minor role for T and B cells in the aetiology of the disease (Fig. 5b). Consistent with the proposed function in the aetiology of the disease we found strong upregulation of S100A8 and S100A9 in the epidermis of Rag2-deficient mice lacking JunB and c-Jun (Fig. 5c, d). Notably, these mice showed a similar chemokine/cytokine profile as seen in JunBΔep* c-JunΔep* mice, indicating that T cells are not essential in establishing the chemokine/cytokine profile seen in psoriasis (Fig. 5e). In addition, the paws of mutant mice were almost unaffected and the inflammation of the joint regions was strongly reduced. Bone destruction was absent demonstrating that a functional contribution of immune cells was a prerequisite for the development of arthritic lesions (Fig. 5b).
Development of psoriatic arthritis requires TNF signalling
Recently developed biological agents reported to improve psoriasis and psoriatic arthritis are directed towards inhibiting TNF-α signalling22. To analyse the contribution of TNFα-signalling through TNFR1 in the progression of psoriasis and psoriatic arthritis, we induced deletion of JunB and c-Jun in mice deficient for TNFR1. Deletion of TNFR1 in JunB/c-Jun double-mutant mice could not prevent the development of the skin phenotype, although histological analyses showed a significantly milder phenotype when compared to JunB/c-Jun double-mutant mice (Fig. 5a, b). Expression of S100A8 and S100A9 was strongly upregulated (Fig. 5c, d) and a chemokine/cytokine profile comparable to JunBΔep* c-JunΔep* mice was observed, suggesting that TNFR-1 signalling is dispensable for the aetiology of the disease (Fig. 5e). However, the inflammation of the joint regions was again almost absent demonstrating a functional contribution of TNF-α signalling through TNFR1 to the aetiology of the arthritic lesions. These results provide strong genetic evidence that the development of the skin phenotype does not fully depend on T-cells or TNF-α signalling through TNFR1, although both are contributors to the disease development and severity.
Research into the pathogenesis of psoriasis has been hampered by the lack of an animal disease resembling this common human skin disorder1. Previous attempts to faithfully reproduce the psoriatic phenotype through expression of inflammatory mediators or keratinocyte growth factors like amphiregulin23, TNF-α (ref. 24), IL-1α (ref. 25), IFN-γ (ref. 26), KGF27, VEGF28, TGF-β1 (ref. 29), Stat3 (ref. 30) and others28 gave rise to phenotypes with only partial resemblance to psoriasis. Moreover, almost all mouse models discussed above showed no arthritic lesions, although these are present in up to 40% of patients with psoriasis.
Many of the histological and molecular hallmarks of psoriatic skin lesions and arthritis are strikingly reproduced in the animals with deletions of JunB and c-Jun in epidermal cells. The phenotype that rapidly develops with 100% penetrance closely resembles the clinical and histological picture of human psoriasis. The disease is prominent in hairless areas of the skin (ears, paws and tail), but is also present in hairy, back skin and the symmetrical distribution is reminiscent of that of psoriatic lesions in humans. Arthritic lesions strongly reminiscent of psoriatic arthritis characterized by inflammatory infiltrates along with massive bone destructions were observed with 100% penetrance. The diseased epidermis mirrored the changes in the cytokine and chemokine network reported for psoriasis. Expression profiling revealed further evidence that the change in gene expression resembled most of the documented genetic changes described for psoriasis. As in the mouse model an inverse expression pattern for the chemotactic proteins S100A8 and S100A9 (ref. 16) and JunB was found in unaffected and affected areas of skin biopsies from psoriatic patients. These proteins are considered to be potential mediators in psoriasis, because their genes are located in the psoriasis susceptibility region PSORS4 (1q12; ref. 31). Moreover, the increased expression of the chemotactic proteins S100A8 and S100A9 was identified as an early event in the development of the phenotype, well before any histological alterations or deregulation of other cytokines was observed (Fig. 4c). In addition, strongly increased expression of S100A8 and S100A9 was seen on deletion of JunB and c-Jun in cultured keratinocytes, suggesting regulation of both genes by Jun proteins (Fig. 4e). Both proteins are potent stimulators of neutrophils32 and passive immunization against S100A8 and S100A9 inhibited neutrophil migration in response to lipopolysaccharide (LPS) injection33. Therefore, induced chemotaxis of neutrophils by S100A8 and S100A9 on deletion of JunB and c-Jun can be envisaged as a decisive early event in the establishment of the psoriatic phenotype.
It is interesting to note that in humans, downregulation of JunB alone in the epidermis appears to be the critical factor in the aetiology of psoriasis, whereas in mice, the deletion of both AP-1 components are necessary. This result may be explained by different expression patterns of AP-1 components in the skin of human and mouse, indicating both overlaps and differences in the biological functions of distinct AP-1 proteins34. Reduced AP-1 binding activity was recently reported in lesional skin from psoriatic patients35. However, it is currently unknown whether the reduced epidermal expression of JunB in psoriasis is caused by transcriptional or post-transcriptional regulation. Preliminary experiments using light-cycler RT–PCR with RNA from patients showed no significant changes in RNA levels between affected and unaffected epidermis (data not shown). This may imply that the regulation occurs at the level of altered protein turnover, a mechanism that was recently described for JunB in T cells36,37.
It has been discussed that certain forms of psoriasis, such as the juvenile form, can be triggered by bacterial infections21. Therefore, we tested whether treatment of mutant mice with the broad-spectrum antibiotic ciprofloxacin affects the development of the phenotype. Interestingly, preliminary data show that ciprofloxacin significantly delayed the onset of the disease and it seems that the arthritic phenotype did not develop (see Supplementary Fig. 4). This implies that resident bacteria might be responsible for the manifestation of the joint disease in our mouse model.
For several years it has been discussed whether psoriasis represents a fundamental disorder of the skin or the immune system. The presence of T cells does not necessarily implicate a critical participation in the aetiology of the disease and no experiments have been performed in which skin of a healthy individual was forced to exhibit a psoriatic phenotype by transplantation of only T cells38,39. Moreover, it is known that other cell types react in response to so-called T-cell-specific drugs. Cyclosporin A for example has effects on neutrophils40 and can inhibit keratinocyte proliferation induced by epidermal growth factor (EGF), TGF-α or IL-6 (ref. 41). Another argument for a functional role of T cells is the association of psoriasis with HLA antigens such as Cw6. Three psoriasis-associated susceptibility alleles have been identified within the PSORS1 locus (HLAC6w, HCR*WWCC and CDSN*5). However, transgenic mice expressing these genes under the control of the keratin 14 (K14) promoter appear phenotypically normal and their skin was histologically indistinguishable from wild-type mice42. Moreover, although psoriasis is thought to be a Th1-induced disorder, it develops in human immunodeficiency virus (HIV) infected patients with the same frequency as in the general population. In fact, the phenotype in patients with pre-existing psoriasis may even be worse and more difficult to treat in the presence of HIV disease. This paradoxical exacerbation of psoriasis in AIDS sufferers has not yet been fully explained43.
Strong genetic evidence against an absolute requirement of T cells in the initial development of psoriasis is provided by the deletion of JunB and c-Jun in a Rag2-deficient background. Under these conditions, histological analyses revealed all the hallmarks of psoriasis, although the skin phenotype was milder when compared to T-cell-competent controls. In addition, a similar chemokine/cytokine profile was observed in Rag2-deficient mice lacking JunB and c-Jun, indicating that T cells are of minor importance in the development of the disease. We envisage that the role of T cells could be to amplify the initial inflammatory response. Interestingly, only small epidermal lesions at the paws were observed and the inflammation in the joint region was strongly reduced indicating a central role of T cells in the pathogenesis of the arthritic lesions.
Cellular proliferation and deregulated cytokine expression are thought to be central in the pathogenesis of psoriasis. JunB/AP-1 is a well known regulator of cytokine production and cellular proliferation. JunB-deficient mouse fibroblasts are hyperproliferative44 and exhibit high basal level expression of cytokines, such as keratinocyte growth factor (KGF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), which promote keratinocyte proliferation in a paracrine fashion45. Moreover, downregulation of JunB in the myeloid compartment caused a chronic myeloid leukaemia (CML)-like disease46,47. The findings described in this study indicate that epidermis-specific modulation of JunB in humans and of JunB/c-Jun in mice induces cytokines/chemokines, which are known to recruit inflammatory cells, thereby contributing to the establishment of the clinical and molecular features observed in psoriasis and psoriatic arthritis. We further provided genetic evidence that the skin disease in mice can develop independently of T cells and that the psoriatic arthritis is primarily mediated by TNF signalling. These data strongly support the recently approved anti-TNFR antibodies as novel therapeutics for psoriasis and psoriatic arthritis.
In summary, we strongly believe that this model with its inducible, high-efficiency and rapid development of the phenotype will be highly suitable for future pre-clinical studies ultimately aimed at understanding and curing this important disease.
Generation of JunBΔep* c-JunΔep* mice
Mice carrying a floxed JunB allele48 (JunBf/f) and/or a floxed c-Jun allele49 (c-Junf/f) were crossed to transgenic mice expressing the Cre recombinase-estrogene receptor fusion under the control of the keratinocyte-specific keratin 5 promoter6 (K5-Cre-ERT) to obtain JunBf/f, c-Junf/f and JunBf/f c-Junf/f K5-Cre-ERT mice.
Inducible deletion of JunB and c-Jun
Eight-week-old mutant mice and their littermate controls were injected daily (intraperitoneal), five times with 1 mg tamoxifen50 (Sigma) or three times with 1 mg tamoxifen (shortened protocol) to obtain epidermis-specific, single- and double-knockout mice.
Adeno-Cre mediated deletion in vitro
Primary keratinocytes were infected (300 particles per cell) with adeno-Cre or adeno-green fluorescent protein (GFP; a gift from M. Cotton) in medium with reduced serum (4% chelated fetal calf serum). After 2 h, normal keratinocyte medium (8% chelated FCS) was added, and after 48 h cells were collected for further analyses.
RNase protection assay and RT–PCR
Epidermis was separated from dermis by trypsin digestion (0.25%) for 1 h at 37 °C. RNase protection assays were performed using the RiboQuant multi-probe RNase protection assay systems mJun/Fos, mck2, mck3 and mck5c (PharMingen) according to the manufacturer's instructions. Standard real-time PCR was performed with the following primers: tubulin-up 5′-CAACGTCAAGACGGCCGTGTG-3′; tubulin-down 5′-ACTGGCGGGGTGTAGGTAAAGGTG-3′; S100A8up 5′-GGAATCACCATGCCCTCTACA-3′; S100A8down 5′-TGCCACGCCCACCCTTATC-3′; S100A9up 5′-GAGCGCAGCATAACCACCATC-3′; S100A9down 5′-AGCCATTCCCTTTAGACTTG-3′; hJunB-up 5′-GCAGGTGGCCCAGCTCAAACAG-3′; hJunB-down 5′-GCCGCGATCGCCCCCTCTT-3′; hc-Jun-up 5′-TTGCGGCCCCGAAACTTGTGC-3′; hc-Jun-down 5′-CTCGGCGAACCCCTCCTGCTCAT-3′.
Human skin biopsies (n = 8, obtained for diagnostic purposes from patients suffering from psoriasis) and mouse tissues were fixed overnight with neutral buffered 4% paraformaldehyde (PFA) at 4 °C and either directly paraffin embedded or after decalcification (bone) in 0.5% EDTA for 12 d. Five-micrometre sections were stained either with hematoxylin and eosin (H&E) or processed further. Staining for anti JunB, CD31, CD3 and F4/80 (Santa Cruz) was performed after antigen-retrieval (Dako; S1699) with the MultiLink Dako system (Dako; E0453) according to the manufacturer's instructions. Expression of S100A8 was detected by immunofluorescence using polyclonal goat antibodies (Santa Cruz; SC 8112) and secondary donkey-anti-goat-Cy3 antibody (Dianova). For nuclear staining H33342 (Calbiochem) was added in a final concentration of 1 µg ml-1 to the secondary antibody dilution. To quantify immunofluorescence signals of JunB and c-Jun in different layers of normal and psoriatic skin the intensity of 30 nuclei of every layer was measured using Metamorph Software. After normalization for the intensity of background staining in every epidermal layer statistical analysis was performed using two-sided t-test, where P < 0.05 was accepted as significant; error bars represent the standard deviation.
cDNA libraries and processing of microarrays
Global gene expression profiling was performed on two different microarrays, comprising: (1) the murine 20 k ArrayTAG (ref. 12; LION Bioscience); and (2) the 22.4 k NIA cDNA collection from the National Institute of Ageing, combining the 15 k NIA clone set13,14 extended by 7.4 k additional sequences15. Labelling of the probes, hybridization of samples and analysis of fluorescent microarray images was performed as described previously14. To account for the systemic error caused by different properties of the fluorescent dyes concerning incorporation, mean brightness and background noise, the hybridizations were performed in duplicate with reversed assignment of fluorescent dyes (‘colour switch’).
Schon, M. P. Animal models of psoriasis—what can we learn from them? J. Invest. Dermatol. 112, 405–410 (1999)
Nickoloff, B. J. & Nestle, F. O. Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities. J. Clin. Invest. 113, 1664–1675 (2004)
Shaulian, E. & Karin, M. AP-1 as a regulator of cell life and death. Nature Cell Biol. 4, E131–E136 (2002)
Eferl, R. & Wagner, E. F. AP-1: a double-edged sword in tumorigenesis. Nature Rev. Cancer 3, 859–868 (2003)
Mehic, D., Bakiri, L., Ghannadan, M., Wagner, E. F. & Tschachler, E. Fos and jun proteins are specifically expressed during differentiation of human keratinocytes. J. Invest. Dermatol. 124, 212–220 (2005)
Brocard, J. et al. Spatio-temporally controlled site-specific somatic mutagenesis in the mouse. Proc. Natl Acad. Sci. USA 94, 14559–14563 (1997)
Bonifati, C. & Ameglio, F. Cytokines in psoriasis. Int. J. Dermatol. 38, 241–251 (1999)
Uyemura, K., Yamamura, M., Fivenson, D. F., Modlin, R. L. & Nickoloff, B. J. The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response. J. Invest. Dermatol. 101, 701–705 (1993)
Kong, J. & Li, Y. C. Upregulation of interleukin-18 expression in mouse primary keratinocytes induced to differentiate by calcium. Arch. Dermatol. Res. 294, 370–376 (2002)
Lee, E. et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J. Exp. Med. 199, 125–130 (2004)
Hashimoto, K. Regulation of keratinocyte function by growth factors. J. Dermatol. Sci. 24, S46–S50 (2000)
Schlingemann, J. et al. Profile of gene expression induced by the tumour promotor TPA in murine epithelial cells. Int. J. Cancer 104, 699–708 (2003)
Tanaka, T. S. et al. Genome-wide expression profiling of mid-gestation placenta and embryo using a 15,000 mouse developmental cDNA microarray. Proc. Natl Acad. Sci. USA 97, 9127–9132 (2000)
Florin, L. et al. Identification of novel AP-1 target genes in fibroblasts regulated during cutaneous wound healing. Oncogene 23, 7005–7017 (2004)
VanBuren, V. et al. Assembly, verification and initial annotation of the NIA mouse 7.4K cDNA clone set. Genome Res. 12, 1999–2003 (2002)
Broome, A. M., Ryan, D. & Eckert, R. L. S100 protein subcellular localization during epidermal differentiation and psoriasis. J. Histochem. Cytochem. 51, 675–685 (2003)
Waseem, A. et al. Keratin 15 expression in stratified epithelia: downregulation in activated keratinocytes. J. Invest. Dermatol. 112, 362–369 (1999)
Campbell, L. et al. Downregulation and altered spatial pattern of caveolin-1 in chronic plaque psoriasis. Br. J. Dermatol. 147, 701–709 (2002)
Apte, S. S., Olsen, B. R. & Murphy, G. The gene structure of tissue inhibitor of metalloproteinases (TIMP)-3 and its inhibitory activities define the distinct TIMP gene family. J. Biol. Chem. 270, 14313–14318 (1995)
Black, R. A. TIMP3 checks inflammation. Nature Genet. 36, 934–935 (2004)
Nickoloff, B. J. et al. Is psoriasis a T-cell disease? Exp. Dermatol. 9, 359–375 (2000)
Galadari, H., Fuchs, B. & Lebwohl, M. Newly available treatments for psoriatic arthritis and their impact on skin psoriasis. Int. J. Dermatol. 42, 231–237 (2003)
Cook, P. W., Pittelkow, M. R. & Piepkorn, M. Overexpression of amphiregulin in the epidermis of transgenic mice induces a psoriasis-like cutaneous phenotype. J. Invest. Dermatol. 113, 860 (1999)
Cheng, J. et al. Cachexia and graft-vs.-host-disease-type skin changes in keratin promoter-driven TNF alpha transgenic mice. Genes Dev. 6, 1444–1456 (1992)
Groves, R. W., Mizutani, H., Kieffer, J. D. & Kupper, T. S. Inflammatory skin disease in transgenic mice that express high levels of interleukin 1 α in basal epidermis. Proc. Natl Acad. Sci. USA 92, 11874–11878 (1995)
Carroll, J. M., Crompton, T., Seery, J. P. & Watt, F. M. Transgenic mice expressing IFN-gamma in the epidermis have eczema, hair hypopigmentation, and hair loss. J. Invest. Dermatol. 108, 412–422 (1997)
Guo, L., Yu, Q. C. & Fuchs, E. Targeting expression of keratinocyte growth factor to keratinocytes elicits striking changes in epithelial differentiation in transgenic mice. EMBO J. 12, 973–986 (1993)
Xia, Y. P. et al. Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis. Blood 102, 161–168 (2003)
Li, A. G., Wang, D., Feng, X. H. & Wang, X. J. Latent TGFβ1 overexpression in keratinocytes results in a severe psoriasis-like skin disorder. EMBO J. 23, 1770–1781 (2004)
Sano, S. et al. Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nature Med. 11, 43–49 (2005)
Semprini, S. et al. Evidence for differential S100 gene over-expression in psoriatic patients from genetically heterogeneous pedigrees. Hum. Genet. 111, 310–313 (2002)
Ryckman, C., Vandal, K., Rouleau, P., Talbot, M. & Tessier, P. A. Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8/A9 induce neutrophil chemotaxis and adhesion. J. Immunol. 170, 3233–3242 (2003)
Vandal, K. et al. Blockade of S100A8 and S100A9 suppresses neutrophil migration in response to lipopolysaccharide. J. Immunol. 171, 2602–2609 (2003)
Angel, P., Szabowski, A. & Schorpp-Kistner, M. Function and regulation of AP-1 subunits in skin physiology and pathology. Oncogene 20, 2413–2423 (2001)
Johansen, C., Kragballe, K., Rasmussen, M., Dam, T. N. & Iversen, L. Activator protein 1 DNA binding activity is decreased in lesional psoriatic skin compared with nonlesional psoriatic skin. Br. J. Dermatol. 151, 600–607 (2004)
Fang, D. et al. Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation. Nature Immunol. 3, 281–287 (2002)
Gao, M. et al. Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch. Science 306, 271–275 (2004)
Nickoloff, B. J. The search for pathogenic T cells and the genetic basis of psoriasis using a severe combined immunodeficient mouse model. Cutis 65, 110–114 (2000)
Boyman, O. et al. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumour necrosis factor-alpha. J Exp Med 199, 731–736 (2004)
Janco, R. L. & English, D. Cyclosporine and human neutrophil function. Transplantation 35, 501–503 (1983)
Karashima, T., Hachisuka, H. & Sasai, Y. FK506 and cyclosporin A inhibit growth factor-stimulated human keratinocyte proliferation by blocking cells in the G0/G1 phases of the cell cycle. J. Dermatol. Sci. 12, 246–254 (1996)
Elomaa, O. et al. Transgenic mouse models support HCR as an effector gene in the PSORS1 locus. Hum. Mol. Genet. 13, 1551–1561 (2004)
Namazi, M. R. Paradoxical exacerbation of psoriasis in AIDS: proposed explanations including the potential roles of substance P and gram-negative bacteria. Autoimmunity 37, 67–71 (2004)
Passegue, E. & Wagner, E. F. JunB suppresses cell proliferation by transcriptional activation of p16(INK4a) expression. EMBO J. 19, 2969–2979 (2000)
Szabowski, A. et al. c-Jun and JunB antagonistically control cytokine-regulated mesenchymal-epidermal interaction in skin. Cell 103, 745–755 (2000)
Passegue, E., Jochum, W., Schorpp-Kistner, M., Mohle-Steinlein, U. & Wagner, E. F. Chronic myeloid leukemia with increased granulocyte progenitors in mice lacking junB expression in the myeloid lineage. Cell 104, 21–32 (2001)
Passegue, E., Wagner, E. F. & Weissman, I. L. JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells. Cell 119, 431–443 (2004)
Kenner, L. et al. Mice lacking JunB are osteopenic due to cell-autonomous osteoblast and osteoclast defects. J. Cell Biol. 164, 613–623 (2004)
Behrens, A. et al. Impaired postnatal hepatocyte proliferation and liver regeneration in mice lacking c-jun in the liver. EMBO J. 21, 1782–1790 (2002)
Vasioukhin, V., Degenstein, L., Wise, B. & Fuchs, E. The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin. Proc. Natl Acad. Sci. USA 96, 8551–8556 (1999)
We are grateful to M. Sibilia, G. Stingl, D. Maurer, J. Smolen, G. Schett and A. Rot for critical comments and suggestions to the manuscript, M. Cotton for providing adeno-Cre viruses, H. Tkadletz for help in preparing the illustrations and J. Hess for support with S100 protein expression analyses. The IMP is funded by Boehringer Ingelheim and this work was supported by grants from the Austrian Research Foundation, the Deutsche Forschungsgemeinschaft and by the Research Training Network (RTN) Program of the European Community.
No psoriasis following single epidermal deletion of either JunB or c-Jun. (JPG 246 kb)
Cytokine expression after 4 days following three Tam injections. (JPG 364 kb)
Cytokine expression after 18 days following Tam injections. (JPG 111 kb)
Induction of JunB/c-Jun deletion in the presence of ciprofloxacin. (JPG 1140 kb)
Text to accompany the above Supplementary Figures. (DOC 21 kb)
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