No abstract

The interleukin (IL)-1 family members IL-1α, -1β, and -18 are potent inflammatory cytokines whose activities are dependent on heterodimeric receptors of the IL-1R superfamily, and which are regulated by soluble antagonists. Recently, several new IL-1 family members have been identified. To determine the role of one of these family members in the skin, transgenic mice expressing IL1F6 in basal keratinocytes were generated. IL1F6 transgenic mice exhibit skin abnormalities that are dependent on IL-1Rrp2 and IL-1RAcP, which are two members of the IL-1R family. The skin phenotype is characterized by acanthosis, hyperkeratosis, the presence of a mixed inflammatory cell infiltrate, and increased cytokine and chemokine expression. Strikingly, the combination of the IL-1F6 transgene with an IL1F5 deficiency results in exacerbation of the skin phenotype, demonstrating that IL-1F5 has antagonistic activity in vivo. Skin from IL1F6 transgenic, IL1F5−/− pups contains intracorneal and intraepithelial pustules, nucleated corneocytes, and dilated superficial dermal blood vessels. Additionally, expression of IL1RL2, -1F5, and -1F6 is increased in human psoriatic skin. In summary, dysregulated expression of novel agonistic and antagonistic IL-1 family member ligands can promote cutaneous inflammation, revealing potential novel targets for the treatment of inflammatory skin disorders.

IL-36␣ (IL-1F6), IL-36␤ (IL-1F8

Psoriasis is a common immune-mediated disease in European populations; it is characterized by inflammation and altered epidermal differentiation leading to redness and scaling. T cells are thought to be the main driver, but there is also evidence for an epidermal contribution. In this article, we show that treatment of mouse skin overexpressing the IL-1 family member, IL-1F6, with phorbol ester leads to an inflammatory condition with macroscopic and histological similarities to human psoriasis. Inflammatory cytokines thought to be important in psoriasis, such as TNF-α, IL-17A, and IL-23, are upregulated in the mouse skin. These cytokines are induced by and can induce IL-1F6 and related IL-1 family cytokines. Inhibition of TNF or IL-23 inhibits the increased epidermal thickness, inflammation, and cytokine production. Blockade of IL-1F6 receptor also resolves the inflammatory changes in human psoriatic lesional skin transplanted onto immunodeficient mice. These data suggest a role for IL-1F family members in psoriasis.

RANK and RANKL, the key regulators of osteoclast differentiation and activation, also play an important role in the control of proliferation and differentiation of mammary epithelial cells during pregnancy. Here, we show that RANK protein expression is strictly regulated in a spatial and temporal manner during mammary gland development. RANK overexpression under the control of the mouse mammary tumor virus (MMTV) promoter in a transgenic mouse model results in increased mammary epithelial cell proliferation during pregnancy, impaired differentiation of lobulo-alveolar structures, decreased expression of the milk proteins ␤-casein and whey acidic protein, and deficient lactation. We also show that treatment of three-dimensional in vitro cultures of primary mammary cells from MMTV-RANK mice with RANKL results in increased proliferation and decreased apoptosis in the luminal area, resulting in bigger acini with filled lumens. Taken together, these results suggest that signaling through RANK not only promotes proliferation but also inhibits the terminal differentiation of mammary epithelial cells. Moreover, the increased proliferation and survival observed in a three-dimensional culture system suggests a role for aberrant RANK signaling during breast tumorigenesis.The tumor necrosis factor (TNF) family member RANKL and its receptor RANK are key regulators of osteoclast differentiation and activation (16,30). The balance between RANKL, RANK, and osteoprotegerin (OPG), a soluble decoy receptor that competes with RANK for binding to RANKL (32), regulates osteoclast differentiation and activation and therefore bone remodeling and mobilization of calcium from the skeleton (27). In mice, RANK and RANKL are also essential for the development of the mammary gland during pregnancy (18), in particular, for the formation of lobuloalveolar structures after pregnancy day 14 (P14) which are required for a functional lactating mammary gland.Deregulation in the RANKL/OPG system has been reported in malignant bone disease including bone metastasis and humoral hypercalcemia of malignancy (13,21,23). Numerous lines of evidence in animal models indicate that blocking RANK/RANKL interaction effectively prevents tumor-induced hypercalcemia or reduces tumor-induced bone lesions, due to its critical role in osteoclast differentiation and activation (reviewed in references 38 and 41). While RANK expression has been detected in breast cancer lines and in primary tumors including breast tumors (45) and may play a functional role in tumor cell migration and metastasis to the bone (24), it is not clear whether activation of the RANK/RANKL pathway may also contribute to primary tumor growth.The mammary gland defects observed in RANK-and RANKL-deficient mice support the notion that the RANK/ RANKL pathway plays an active role in mammary cell proliferation and survival; however, the direct effect of increased RANK signaling in mammary cells is unknown. To determine if activation of the RANK/RANKL pathway can directly increase proliferation or surv...