Dermatitis due to epiregulin deficiency and a critical role of epiregulin in immune-related responses of keratinocyte and macrophage

Abstract

Epidermal growth factor (EGF) family members, including epiregulin (EP), play a fundamental role in epithelial tissues; however, their roles in immune responses and the physiological role of EP remain to be elucidated. The skin has a versatile system of immune surveillance. Biologically active IL-1␣ is released to extracellular space upon damage from keratinocytes and is a major player in skin inflammation. Here, we show that EP is expressed not only in keratinocytes but also in tissue-resident macrophages, and that EP-deficient (EP ؊/؊ ) mice develop chronic dermatitis. Wound healing in the skin in EP ؊/؊ mice was not impaired in vivo, nor was the growth rate of keratinocytes from EP ؊/؊ mice different from that of WT mice in vitro. Of interest is that in WT keratinocytes, both IL-1␣ and the secreted form of EP induced down-regulation of IL-18 mRNA expression, which overexpression in the epidermis was reported to induce skin inflammation in mice, whereas the downregulation of IL-18 induced by IL-1␣ was impaired in EP ؊/؊ keratinocytes. Although bone marrow transfer experiments indicated that EP deficiency in non-bone-marrow-derived cells is essential for the development of dermatitis, production of proinflammatory cytokines by EP ؊/؊ macrophages in response to Toll-like receptor agonists was much lower, compared with WT macrophages, whose dysfunction in EP ؊/؊ macrophages was not compensated by the addition of the secreted form of EP. These findings, taken together, suggested that EP plays a critical role in immune͞inflammatory-related responses of keratinocytes and macrophages at the barrier from the outside milieu and that the secreted and membranebound forms of EP have distinct functions.T he system of epidermal growth factor (EGF) superfamily (1) and EGF receptor (EGFR) family, including EGFR (ErbB1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4) (2), play a fundamental role in epithelial tissues. EGF family members, including EGF, transforming growth factor-␣, amphiregulin, heparinbinding EGF (HB-EGF), epiregulin (EP), and other members, regulate these receptors by inducing their homo-and͞or heterooligomerization (2, 3). EGF family members vary in their ability to activate distinct ErbB heterodimers, and this mechanism may, in part, account for the differences in their bioactivities (4-7).The membrane-anchored precursor of the EGF family is enzymatically processed externally to release a mature soluble form that acts as autocrine and͞or paracrine growth factor (8, 9), whereas some members of the EGF family act in the membrane-anchored form (8, 10). A bioactive transmembrane precursor, pro-HB-EGF, was suggested to induce growth inhibition or apoptosis rather than the proliferative response induced by soluble HB-EGF (10). EP (11-17) acts as an autocrine growth factor in normal human keratinocytes in vitro (15); however, its physiological role in vivo still remains to be elucidated.Keratinocytes in the epidermis play critical roles in the cutaneous immune-related responses (18) and contain biologically active ...

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“…In its secreted form, epiregulin stimulated proliferation of keratinocytes in an autocrine and paracrine manner in vitro (Shirakata et al, 2000;Takahashi et al, 2003). Mice deficient in epiregulin-developed dermatitis, further implicating epiregulin in regulating keratinocyte growth in vivo (Shirasawa et al, 2004). High expression levels of the epiregulin gene have been shown in a number of cancer cell lines and activation of the Ki-Ras signaling pathway in colon cancer cells has been linked to the deregulation of epiregulin expression (Baba et al, 2000).…”

“…Among the epidermal growth factor receptor ligands, epiregulin is distinguished by its more potent mitotic activity, the ability to bind various heterodimeric ErbB receptors (Shelly et al, 1998), and its unusual expression pattern, mainly in peripheral blood monocytes, macrophages and the placenta in normal human tissues, as well as in various types of epithelial tumor cell lines (Toyoda et al, 1997). In the mouse, epiregulin is expressed by tissue resident and peritoneal macrophages in vivo and its expression in macrophages is induced in response to the toll-like receptor agonists LPS and peptidoglycan in vitro (Shirasawa et al, 2004). Production of epiregulin by inflammatory macrophages may be a beneficial reaction that helps repair tissue damage at the sites of inflammation.…”

Heparin‐binding epidermal growth factor‐like growth factor as a novel targeting molecule for cancer therapy

“…(30) Betacellulin null mice are viable and display no overt defects, (30) whereas epiregulin null mice are viable but develop chronic dermatitis. (31) Thus, HB-EGF null mice show the most severe phenotypes among the mice with disrupted ligand binding to EGFR. In contrast to TGF-α, EGF and amphiregulin, HB-EGF binds to and activates both EGFR and ErbB4.…”

Protective effect of 2,2,2-trichloroethanol on peptidoglycan-induced inflammation in murine macrophages

“…The TNF-α and IL-6 levels sharply increased at 12 and 24 h after the peptidoglycan-challenge. Similar studies using peptidoglycan (10 or 25 μg/ml) were performed by others (Shirasawa et al, 2004;Wang et al, 2004), but they only tested 24 h after one challenge. Also, the treatments with 2,2,2-trichloroethanol significantly decreased the rise of inflammatory cytokines production (Figure 1).…”