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- W1508931708 abstract "The outermost part of the skin, the epidermis, is built up by cells called keratinocytes. The epidermis provides a vital barrier between the body and the outer world. It is in addition a target for constant physical and microbial injury. Reflecting this, the keratinocytes are not only structural cells but are endowed with a capability to communicate with our immune system in order to eliminate the danger. The constant exposure to the environment also makes the skin vulnerable to carcinogenesis. Squamous Cell Carcinoma (SCC), which originates from the keratinocytes, is the second most common cancer in men, and the third most common in women in Sweden. The transcription factor Nuclear Factor kappa B (NF-κB) plays a crucial role as a coordinator of inflammation, proliferation and apoptosis and is expressed by virtually all cells in our body. Usually, increased NF-κB activity is associated with inflammation and cancer. However, the skin challenges our perspectives on this key player, since both increased and decreased NF-κB activity in the skin, have been linked to the development of inflammatory diseases. Our group has previously shown that inhibition of NF-κB in keratinocytes in mice do not only cause inflammation, but inevitably leads to the development of SCC. Inflammation and rare subungual skin tumours are also seen in the human congenital disease Incontientia Pigmenti (IP). IP is caused by a genetic defect that interferes with NF-κB activation. Our mouse model mimics many aspects of this disease. Inflammation and cancer are intimately linked, and understanding the molecular circuits that set up a pro-tumourigenic inflammatory response is an important task. The work in this thesis aimed to further explore the role of NF-κB in keratinocytes in order to gain new insights to their role in skin immunology and in the development of skin cancer. Paper I: The proinflammatory cytokine Tumour Necrosis Factor alpha (TNFα) has been implicated in several inflammatory diseases and is thought to be crucial for the promotion of tumourigenesis. In this paper we show that signalling mediated by TNFα downstream of its receptor TNF receptor 1 (TNFR1) is necessary both for the development of inflammation and cancer in response to inhibition of NF-κB in keratinocytes. Moreover, we show that the TNFR1 signalling that initiates the disease occurs in non-immune cells. Paper II: In this paper, we investigated the role of NF-κB in keratinocytes growth in culture. We show that whereas normal keratinocytes cease to grow when they are exposed to phorbol esters, keratinocytes with inhibited NF-κB continue to grow. Surprisingly, this effect is TNFR1 independent. In addition to the effects on inflammation, this ability may be a contributing factor to the development of skin cancer in response to NF-κB inhibition. We also demonstrate a TNFR1-independent, aberrant response of NF-κB deficient skin to the treatment of phorbol esters in vivo. Paper III: Besides inflammation, inhibition of NF-κB is linked to defects in the formation of ectodermal appendages such as hair follicles and sweat glands. To be able to distinguish the developmental effects of NF-κB inhibition from its postnatal effects on inflammation and to better be able to follow the temporal induction and progression of the disease, we here took advantage of a conditional mouse model. We demonstrate that induction of inflammation after birth is independent from the developmental effects of NF-κB inhibition. Moreover, we show that F4/80+ inflammatory cells (e.g. macrophages) are the first cells to invade the skin after the onset of NF-κB inhibition and link their infiltration to the cooperative upregulation of three chemokines (MCP-13). Furthermore, our data reveal that the macrophages indirectly contribute to the increased angiogenesis in the inflamed skin by producing Vascular Endothelial Growth Factor (VEGFA). Paper IV: In this paper we demonstrate that TNFR1 expression in keratinocytes alone mediates the inflammatory circuit elicited by inhibition of NF-κB. TNFR1 expression in all other cell types is surprisingly redundant. In addition, we show that TNFR1 expression outside the epithelial compartment in our model of inflammationdriven skin tumourigenesis, is dispensable both for the cellular and molecular signature of the inflammatory response at all stages of tumourigenesis. Our analysis reveals that an inflammatory environment with an immunosuppressive and a tissue remodulatory signature is established early, already in pre-malignant skin. This includes an accumulation of macrophages of an alternative, tumour promoting, M2 type, together with an increase in CD4+CD25+FoxP3+ regulatory T-cells. Unexpectedly, keratinocytes with inhibited NF-κB upregulate the immunosuppressive cytokine Interleukin-10 (IL-10). This may provide a molecular explanation for the early establishment of an immunosuppressive environment in this model. Taken together, our results shed new light on the unique role of the keratinocytes as messenger cells to our immune system and demonstrate how the NF-κB pathway downstream TNFR1 controls this feature. Our discoveries couple TNFα/TNFR1 to skin cancer progression and opens up the prospective use of anti-TNF in skin cancer treatment. LIST OF PUBLICATIONS This thesis is based on the following original articles, which will be referred to in the text by their Roman numerals: I. Lind M.H., Rozell B., Wallin R.P., van Hogerlinden M., Ljunggren H.G., Toftgard R., Sur I. Tumour necrosis factor receptor 1-mediated signalling is required for skin cancer development induced by NF-κB inhibition. (2004) Proceedings of the National Academy of Science United States of America., 101(14): 4972-7. II. Sur I., Ulvmar M., Jungedal R., Toftgard R. Inhibition of NF-κB signalling interferes with phorbol ester-induced growth arrest of keratinocytes in a TNFR1 independent manner. (2009) Journal of Receptors and Signal Transduction, 29(1): 44-51. III. Ulvmar M.H., Sur I., Memet S., Toftgard R. Timed NF-κB inhibition in skin reveals dual independent effects on development of HED/EDA and chronic inflammation. (2009) Journal of Investigative Dermatology, Jun 11, Advanced Online Publication. IV. Ulvmar M.H., Wallin R.P., Sur I, Toftgard R. NF-κB inhibition and skin cancer: a viscous circle of chronic inflammation and immunosuppression driven by TNFR1 in kertinocytes. (2009) Manuscript in preparation." @default.
- W1508931708 created "2016-06-24" @default.
- W1508931708 creator A5011520072 @default.
- W1508931708 date "2009-08-03" @default.
- W1508931708 modified "2023-09-23" @default.
- W1508931708 title "NF-kappaB in skin immune homeostasis and cancer development" @default.
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