c-Jun and JunB Antagonistically Control Cytokine-Regulated Mesenchymal–Epidermal Interaction in Skin

Szabowski, Axel; Maas‐Szabowski, Nicole; Andrecht, Sven; Kolbus, Andrea; Schorpp-Kistner, Marina; Fusenig, Norbert E.; Angel, Peter

doi:10.1016/s0092-8674(00)00178-1

Cited by 386 publications

(333 citation statements)

References 56 publications

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“…IL-1 can act in an autocrine manner, and its release by dying keratinocytes can stimulate further IL-1 production 39 . In addition, it induces production of major keratinocyte mitogens by fibroblasts 45,46 . We found that Aldara also activated the NLRP-1 inflammasome in (human) keratinocytes resulting in caspase-1-dependent production of biologically active IL-1b.…”

Section: Discussionmentioning

confidence: 99%

Aldara activates TLR7-independent immune defence

et al. 2013

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Aldara is a cream used for topical treatment of non-melanoma skin cancer, and is thought to act through stimulation of anti-tumour immunity. The active ingredient, imiquimod, has been shown to stimulate toll-like receptor 7. Aldara also induces psoriasis-like lesions when applied to naive murine skin, and as such is used as a mouse model for psoriasis. Here we find that in naive murine skin, Aldara induces inflammation largely independently of toll-like receptor 7. Surprisingly, inflammasome activation, keratinocyte death and interleukin 1 release also occur in response to the vehicle cream in the absence of imiquimod. We show that isostearic acid, a major component of the vehicle, promotes inflammasome activation in cultured keratinocytes, and so may contribute to the observed effects of Aldara on murine skin. Aldara therefore stimulates at least two immune pathways independently, and both imiquimod and vehicle are required for a full inflammatory response. Although it remains to be tested, it is possible that imiquimod-independent effects also contribute to the therapeutic efficacy of Aldara.

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Section: Discussionmentioning

confidence: 99%

Aldara activates TLR7-independent immune defence

et al. 2013

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“…Norbert Fusenig and colleagues have developed an assay to model the natural tissue context of the stratified skin epithelium 111 . Using this system, they were able to suppress early stages of neoplastic progression of malignant keratinocytes by introducing an excess of normal keratinocytes 112 .…”

Section: Restoring the Normal Contextmentioning

confidence: 99%

Putting tumours in context

2001

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The interactions between cancer cells and their micro-and macroenvironment create a context that promotes tumour growth and protects it from immune attack. The functional association of cancer cells with their surrounding tissues forms a new 'organ' that changes as malignancy progresses. Investigation of this process might provide new insights into the mechanisms of tumorigenesis and could also lead to new therapeutic targets.Under normal conditions, ORGANS are made up of TISSUES that exchange information with other cell types via cell-cell contact, cytokines and the EXTRACELLULAR MATRIX (ECM). The ECM, which is produced by collaboration between STROMAL fibroblasts and EPITHELIAL cells, provides structural scaffolding for cells, as well as contextual information. The endothelial vasculature provides nutrients and oxygen, and cells of the immune system combat pathogens and remove apoptotic cells. Epithelial cells associate into intact, polarized sheets. These tissues communicate through a complex network of interactions: physically, through direct contact or through the intervening ECM, and biochemically, through both soluble and insoluble signalling molecules. In combination, these interactions provide the information that is necessary to maintain cellular differentiation and to create complex tissue structures.Occasionally, the intercellular signals that define the normal context become disrupted. Alterations in epithelial tissues can lead to movement of epithelial sheets and proliferationfor example, after activation of mesenchymal fibroblasts due to wounding. Normally, these conditions are temporary and reversible, but when inflammation is sustained, an escalating feedback loop ensues. Under persistent inflammatory conditions, continual upregulation of enzymes such as matrix metalloproteinases (MMPs) by stromal fibroblasts can disrupt the ECM, and invading immune cells can overproduce factors that promote abnormal proliferation.As this process progresses, the normal organization of the organ is replaced by a functional disorder (FIG. 1). If there are pre-existing epithelial cells within this changing context that possess tumorigenic potential, they can start to proliferate. Alternatively, the abnormal An innate anticancer mechanismAn important feature of the normal stromal context is the generation and maintenance of epithelial-cell polarity. Epithelial cells receive a variety of orientational cues from the environment that help them establish cellular apical and basal surfaces and to maintain the differentiated state. Loss of polarity has been shown to lead to increased cell proliferation and tumorigenesis (BOX 1). The basal surface of epithelial cells associates with the BASEMENT MEMBRANE, a specialized form of ECM that provides both structural support and polarization signals to epithelia. The basement membrane is a dynamic structure. Changes in its composition lead to changes in cell shape and behaviour 1 , altered binding affinity or cellular distribution of cell-surface receptors 2 , and cellu...

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“…It is known that the underlying connective tissue can modulate these events through two mechanisms. First, fibroblast-derived diffusible factors can act in a paracrine fashion to regulate the behavior of basal keratinocytes (Fusenig 1994;Szabowski et al 2000). Secondly, interactions between basement membrane (BM) proteins and adjacent basal keratinocytes at their stem cell niche are known to direct keratinocyte fate decisions (Jones et al 1995).…”

Section: Introductionmentioning

confidence: 99%

The basement membrane microenvironment directs the normalization and survival of bioengineered human skin equivalents

Segal¹,

Andriani²,

Pfeiffer³

et al. 2008

Matrix Biology

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Epithelial-mesenchymal interactions promote the morphogenesis and homeostasis of human skin. However, the role of the basement membrane (BM) during this process is not well-understood. To directly study how BM proteins influence epidermal differentiation, survival and growth, we developed novel 3D human skin equivalents (HSEs). These tissues were generated by growing keratinocytes at an air-liquid interface on polycarbonate membranes coated with individual matrix proteins (Type I Collagen, Type IV Collagen or fibronectin) that were placed on contracted Type I Collagen gels populated with dermal fibroblasts. We found that only keratinocytes grown on membranes coated with the BM protein Type IV Collagen showed optimal tissue architecture that was similar to control tissues grown on de-epidermalized dermis (AlloDerm) that contained intact BM. In contrast, tissues grown on proteins not found in BM, such as fibronectin and Type I Collagen, demonstrated aberrant tissue architecture that was linked to a significant elevation in apoptosis and lower levels of proliferation of basal keratinocytes. While all tissues demonstrated a normalized, linear pattern of deposition of laminin 5, tissues grown on Type IV Collagen showed elevated expression of α6 integrin, Type IV Collagen and Type VII Collagen, suggesting induction of BM organization. Keratinocyte differentiation (Keratin 1 and filaggrin) was not dependent on the presence of BM proteins. Thus, Type IV Collagen acts as a critical microenvironmental factor in the BM that is needed to sustain keratinocyte growth and survival and to optimize epithelial architecture.

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c-Jun and JunB Antagonistically Control Cytokine-Regulated Mesenchymal–Epidermal Interaction in Skin

Cited by 386 publications

References 56 publications

Aldara activates TLR7-independent immune defence

Aldara activates TLR7-independent immune defence

Putting tumours in context

The basement membrane microenvironment directs the normalization and survival of bioengineered human skin equivalents

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