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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.

The skeleton and the immune system share a variety of different cytokines and transcription factors, thereby mutually influencing each other. These interactions are not confined to the bone marrow cavity where bone cells and hematopoietic cells exist in proximity but also occur at locations that are target sites for inflammatory bone diseases. The newly established research area termed 'osteoimmunology' attempts to unravel these skeletal/immunological relationships. Studies towards a molecular understanding of inflammatory bone diseases from an immunological as well as a bone-centered perspective have been very successful and led to the identification of several signaling pathways that are causally involved in inflammatory bone loss. Induction of receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) signals by activated T cells and subsequent activation of the key transcription factors Fos/activator protein-1 (AP-1), NF-kappaB, and NF for activation of T cells c1 (NFATc1) are in the center of the signaling networks leading to osteoclast-mediated bone loss. Conversely, nature has employed the interferon system to antagonize excessive osteoclast differentiation, although this counteracting activity appears to be overruled under pathological conditions. Here, we focus on Fos/AP-1 functions in osteoimmunology, because this osteoclastogenic transcription factor plays a central role in inflammatory bone loss by regulating genes like NFATc1 as well as the interferon system. We also attempt to put potential therapeutic strategies for inflammatory bone diseases in perspective.

To investigate the function of c-Jun during skin development and skin tumor formation, we conditionally inactivated c-jun in the epidermis. Mice lacking c-jun in keratinocytes (c-jun(Deltaep)) develop normal skin but express reduced levels of EGFR in the eyelids, leading to open eyes at birth, as observed in EGFR null mice. Primary keratinocytes from c-jun(Deltaep) mice proliferate poorly, show increased differentiation, and form prominent cortical actin bundles, most likely because of decreased expression of EGFR and its ligand HB-EGF. In the absence of c-Jun, tumor-prone K5-SOS-F transgenic mice develop smaller papillomas, with reduced expression of EGFR in basal keratinocytes. Thus, using three experimental systems, we show that EGFR and HB-EGF are regulated by c-Jun, which controls eyelid development, keratinocyte proliferation, and skin tumor formation.

Activator protein 1 (AP-1) (Fos/Jun) is a transcriptional regulator composed of members of the Fos and Jun families of DNA binding proteins. The functions of AP-1 were initially studied in mouse development as well as in the whole organism through conventional transgenic approaches, but also by gene targeting using knockout strategies. The importance of AP-1 proteins in disease pathways including the inflammatory response became fully apparent through conditional mutagenesis in mice, in particular when employing gene inactivation in a tissue-specific and inducible fashion. Besides the well-documented roles of Fos and Jun proteins in oncogenesis, where these genes can function both as tumor promoters or tumor suppressors, AP-1 proteins are being recognized as regulators of bone and immune cells, a research area termed osteoimmunology. In the present article, we review recent data regarding the functions of AP-1 as a regulator of cytokine expression and an important modulator in inflammatory diseases such as rheumatoid arthritis, psoriasis and psoriatic arthritis. These new data provide a better molecular understanding of disease pathways and should pave the road for the discovery of new targets for therapeutic applications. IntroductionThe transcription factor activator protein 1 (AP-1) consists of dimers composed of members of the Jun, Fos and activating transcription factor protein families. In contrast to the Fos proteins (Fos, FosB, Fra-1 and Fra-2), which can only heterodimerize with members of the Jun family, Jun family members (Jun, JunB and JunD) can homodimerize and heterodimerize with Fos members [1]. In addition, some members of the activating transcription factor and cAMP response elementbinding protein families also dimerize with the core members of the AP-1 family to regulate a broad variety of genes [2] by binding to their promoter and enhancer regions (Figure 1).Although members of the Jun and Fos families share a high degree of structural homology, the individual AP-1 dimers exert significant differences in their DNA binding affinity and their capability to activate or suppress gene expression [3]. AP-1 converts extracellular signals of evolutionary conserved signaling pathways like mitogen-activated protein kinase, transforming growth factor beta and Wnt into changes in the expression of specific target genes that harbor AP-1 binding sites. Growth factors, neurotransmitters, polypeptide hormones, bacterial and viral infections as well as a variety of physical and chemical stresses employ AP-1 to translate external stimuli both into short-term and long-term changes of gene expression. These stimuli activate mitogen-activated protein kinase cascades that enhance AP-1 activity; for example, through phosphorylation of distinct substrates [4]. Activator protein 1 functions in miceMany important insights regarding the specific functions of AP-1 proteins in development and disease have been obtained from genetically modified mice and the cells derived thereof (Table 1) [1,2]. In the following s...

The AP-1 transcription factor c-Jun is a key regulator of hepatocyte proliferation. Mice lacking c-Jun in the liver (c-jun ⌬li* ) display impaired liver regeneration after partial hepatectomy (PH). This phenotype correlates with increased protein levels of the cdk-inhibitor p21 in the liver. We performed PH experiments in several double-knockout mouse models to genetically identify the signaling events regulated by c-Jun. Inactivation of p53 in c-jun ⌬li* mice abrogated both hepatocyte cell cycle block and increased p21 protein expression. Consistently, liver regeneration was rescued in c-jun ⌬li* p21 −/− double-mutant mice. This indicated that c-Jun controls hepatocyte proliferation by a p53/p21-dependent mechanism. Analyses of p21 mRNA and protein expression in livers of c-jun ⌬li* mice after PH revealed that the accumulation of p21 protein is due to a post-transcriptional/post-translational mechanism. We have investigated several candidate pathways implicated in the regulation of p21 expression, and observed increased activity of the stress kinase p38 in regenerating livers of c-jun ⌬li* mice. Importantly, conditional deletion of p38␣ in livers of c-jun ⌬li* mice fully restored hepatocyte proliferation and attenuated increased p21 protein levels after PH. These data demonstrate that c-Jun/AP-1 regulates liver regeneration through a novel molecular pathway that involves p53, p21, and the stress kinase p38␣.[Keywords: c-Jun; p53; p21; p38/liver regeneration; partial hepatectomy] Supplemental material is available at http://www.genesdev.org. Liver regeneration triggered by two-third partial hepatectomy (PH) is a well-established model system in rodents for studying the molecular mechanisms of cell cycle control. Hepatocytes that are normally quiescent and highly differentiated cells enter the S-phase rapidly after surgery and undergo one to two rounds of replication in order to fully restore liver mass (Diehl 2002;Fausto 2004;Taub 2004). Importantly, abnormal regeneration contributes to the pathogenesis of fulminant liver failure, cirrhosis, and primary liver cancer. Initiation of liver regeneration occurs when hepatocytes are primed to synchronously escape quiescence and enter the prereplicative phase of the cell cycle (G1) after PH (Fausto 2004). The priming phase is controlled by several cytokines such as tumor necrosis factor ␣ (TNF␣) and Interleukin-6 (IL-6) (Akerman et al. 1992;Cressman et al. 1996;Yamada et al. 1997). Cytokines activate a variety of transcription factors important during the initial stages of liver regeneration, including nuclear factor-B (NF-B), signal transducer and activator of transcription 3 (STAT3), CCAAT enhancer-binding protein ␤ (C/EBP␤), and activator protein 1 (AP-1) (Cressman et al. 1995;FitzGerald et al. 1995;Heim et al. 1997;Greenbaum et al. 1998). At later stages hepatocyte growth factor (HGF), transforming growth factor ␣ (TGF␣), and heparin-binding epidermal growth factor (HB-EGF) stimulate S-phase entry of hepatocytes (Mead and Fausto 1989;Borowiak et al. 2004;Huh et al....

Mice lacking the AP-1 transcription factor c-Jun die around embryonic day E13.0 but little is known about the cell types affected as well as the cause of embryonic lethality. Here we show that a fraction of mutant E13.0 fetal livers exhibits extensive apoptosis of both hematopoietic cells and hepatoblasts, whereas the expression of 15 mRNAs, including those of albumin, keratin 18, hepatocyte nuclear factor 1, β-globin, and erythropoietin, some of which are putative AP-1 target genes, is not affected. Apoptosis of hematopoietic cells in mutant livers is most likely not due to a cell-autonomous defect, since c-jun −/− fetal liver cells are able to reconstitute all hematopoietic compartments of lethally irradiated recipient mice. A developmental analysis of chimeras showed contribution of c-jun −/− ES cell derivatives to fetal, but not to adult livers, suggesting a role of c-Jun in hepatocyte turnover. This is in agreement with the reduced mitotic and increased apoptotic rates found in primary liver cell cultures derived from c-jun −/− fetuses. Furthermore, a novel function for c-Jun was found in heart development. The heart outflow tract of c-jun −/− fetuses show malformations that resemble the human disease of a truncus arteriosus persistens. Therefore, the lethality of c-jun mutant fetuses is most likely due to pleiotropic defects reflecting the diversity of functions of c-Jun in development, such as a role in neural crest cell function, in the maintenance of hepatic hematopoiesis and in the regulation of apoptosis.

Studies using genetically modified mice have revealed fundamental functions of the transcription factor Fos/AP-1 in bone biology, inflammation, and cancer. However, the biological role of the Fos-related protein Fra-2 is not well defined in vivo. Here we report an unexpected profibrogenic function of Fra-2 in transgenic mice, in which ectopic expression of Fra-2 in various organs resulted in generalized fibrosis with predominant manifestation in the lung. The pulmonary phenotype was characterized by vascular remodeling and obliteration of pulmonary arteries, which coincided with expression of osteopontin, an AP-1 target gene involved in vascular remodeling and fibrogenesis. These alterations were followed by inflammation; release of profibrogenic factors, such as IL-4, insulin-like growth factor 1, and CXCL5; progressive fibrosis; and premature mortality. Genetic experiments and bone marrow reconstitutions suggested that fibrosis developed independently of B and T cells and was not mediated by autoimmunity despite the marked inflammation observed in transgenic lungs. Importantly, strong expression of Fra-2 was also observed in human samples of idiopathic and autoimmune-mediated pulmonary fibrosis. These findings indicate that Fra-2 expression is sufficient to cause pulmonary fibrosis in mice, possibly by linking vascular remodeling and fibrogenesis, and suggest that Fra-2 has to be considered a contributing pathogenic factor of pulmonary fibrosis in humans.fra-2 transgenic mouse ͉ idiopathic pulmonary fibrosis ͉ osteopontin ͉ pulmonary arterial hypertension ͉ fibrosis mouse model