Abstract:Epithelial cells of the airways can, under pathological conditions, undergo squamous metaplasia. The accumulation of cholesterol sulfate has recently been described as a new marker for squamous cell differentiation in rabbit tracheal epithelial cells. We now report that normal human bronchial epithelial cells in culture metabolically incorporated [35S]-sulfate and [3H]-mevalonate into material indistinguishable from cholesterol sulfate by the criteria of solubility in organic solvents, behavior on ion-exchange… Show more
“…Cholesterol sulfate is present in various tissues and body fluids, and it accumulates during squamous cell differentiation in the epithelial cells of barrier tissues, such as the respiratory tract and esophageal mucosa (11,12,42). Cholesterol sulfate is also found in considerable quantities in the skin, predominantly in the epidermis (10), where it acts as an important regulator during the formation of the epidermal barrier (42).…”
Section: Discussionmentioning
confidence: 99%
“…Assuming that Mincle may be an important sensor of tissue damage, we performed a search for new endogenous ligands of this receptor. Using chromatography and mass spectrometry, we found that cholesterol sulfate, an abundant molecule in the epithelial barrier layers in the skin and gastrointestinal and respiratory tracts (10)(11)(12), is selectively recognized by Mincle. Here, we show that Mincle activation by cholesterol sulfate causes the secretion of a range of proinflammatory mediators and that s.c. injection of cholesterol sulfate results in a Minclemediated induction of a severe local inflammatory response.…”
Sterile (noninfected) inflammation underlies the pathogenesis of many widespread diseases, such as allergies and autoimmune diseases. The evolutionarily conserved innate immune system is considered to play a key role in tissue injury recognition and the subsequent development of sterile inflammation; however, the underlying molecular mechanisms are not yet completely understood. Here, we show that cholesterol sulfate, a molecule present in relatively high concentrations in the epithelial layer of barrier tissues, is selectively recognized by Mincle (Clec4e), a C-type lectin receptor of the innate immune system that is strongly up-regulated in response to skin damage. Mincle activation by cholesterol sulfate causes the secretion of a range of proinflammatory mediators, and s.c. injection of cholesterol sulfate results in a Mincle-mediated induction of a severe local inflammatory response. In addition, our study reveals a role of Mincle as a driving component in the pathogenesis of allergic skin inflammation. In a well-established model of allergic contact dermatitis, the absence of Mincle leads to a significant suppression of the magnitude of the skin inflammatory response as assessed by changes in ear thickness, myeloid cell infiltration, and cytokine and chemokine secretion. Taken together, our results provide a deeper understanding of the fundamental mechanisms underlying sterile inflammation.innate immunity | sterile inflammation | allergy | Mincle | cholesterol sulfate
“…Cholesterol sulfate is present in various tissues and body fluids, and it accumulates during squamous cell differentiation in the epithelial cells of barrier tissues, such as the respiratory tract and esophageal mucosa (11,12,42). Cholesterol sulfate is also found in considerable quantities in the skin, predominantly in the epidermis (10), where it acts as an important regulator during the formation of the epidermal barrier (42).…”
Section: Discussionmentioning
confidence: 99%
“…Assuming that Mincle may be an important sensor of tissue damage, we performed a search for new endogenous ligands of this receptor. Using chromatography and mass spectrometry, we found that cholesterol sulfate, an abundant molecule in the epithelial barrier layers in the skin and gastrointestinal and respiratory tracts (10)(11)(12), is selectively recognized by Mincle. Here, we show that Mincle activation by cholesterol sulfate causes the secretion of a range of proinflammatory mediators and that s.c. injection of cholesterol sulfate results in a Minclemediated induction of a severe local inflammatory response.…”
Sterile (noninfected) inflammation underlies the pathogenesis of many widespread diseases, such as allergies and autoimmune diseases. The evolutionarily conserved innate immune system is considered to play a key role in tissue injury recognition and the subsequent development of sterile inflammation; however, the underlying molecular mechanisms are not yet completely understood. Here, we show that cholesterol sulfate, a molecule present in relatively high concentrations in the epithelial layer of barrier tissues, is selectively recognized by Mincle (Clec4e), a C-type lectin receptor of the innate immune system that is strongly up-regulated in response to skin damage. Mincle activation by cholesterol sulfate causes the secretion of a range of proinflammatory mediators, and s.c. injection of cholesterol sulfate results in a Mincle-mediated induction of a severe local inflammatory response. In addition, our study reveals a role of Mincle as a driving component in the pathogenesis of allergic skin inflammation. In a well-established model of allergic contact dermatitis, the absence of Mincle leads to a significant suppression of the magnitude of the skin inflammatory response as assessed by changes in ear thickness, myeloid cell infiltration, and cytokine and chemokine secretion. Taken together, our results provide a deeper understanding of the fundamental mechanisms underlying sterile inflammation.innate immunity | sterile inflammation | allergy | Mincle | cholesterol sulfate
“…However, when these cells are cultured on feeder layers, a subpopulation of type A cells is maintained (140)(141)(142). Tracheobronchial epithelial cells in monolayer culture appear largely to behave like population B cells (64,86,87,143 (145). Diacylglycerol, the endogeneous activator of protein kinase C, produces many of the same effects reported for phorbol esters (146).…”
Section: Phorbol Estersmentioning
confidence: 87%
“…In the multistep program of squamous cell differentiation proposed in Figure 2 retinoids affect very specific stages of squamous differentiation whereas other stages are insensitive to retinoids. Retinoids do not block the commitment to terminal cell division in tracheobronchial or epidermal cells induced by confluence, withdrawal of EGF and insulin or addition of TGF-P or PMA (43,64,73); however, retinoids do block the expression of the differentiated phenotype. Retinoids inhibit the induction of transglutaminase type I (54,(99)(100)(101)(102) and cholesterol sulfotransferase activities, inhibit the accumulation of cholesterol sulfate (63)(64)(65)(66), and inhibit cornification in several in vitro tracheobronchial and epidermal cell systems (39,43,(103)(104)(105) (115,116).…”
Section: Action Of Retinoidsmentioning
confidence: 87%
“…Recently, the accumulation of cholesterol sulfate has been shown to be associated with squamous cell differentiation in tracheobronchial and epidermal epithelial cells in culture (63)(64)(65). The increase in cholesterol sulfate has been related to an increase in the enzyme cholesterol sulfotransferase (68).…”
Section: Clonogenic Tracheobronchial Epithelial Cells Are Pluripotentmentioning
The lung, in particular the bronchial epithelium, is a major site for tumor formation in humans. Environmental factors, such as cigarette smoke, in conjunction with genetic factors are important determinants in this disease. Malignant cells exhibit alterations in their control of proliferation and differentiation. It is believed that the acquisition of defects in the regulation of these processes is important in the process of carcinogenesis. A clear insight into the basic mechanisms of the regulation of proliferation and differentiation is required to understand the molecular mechanisms involved in tumor development and in other pathological conditions. Studies using in vitro cell culture systems of tracheobronchial epithelial cells provide useful models in which to study the regulation of differentiation and proliferation. The clonogenic cells derived from the treacheobronchial epithelium are pluripotent: They have self-renewal capacity and can differentiate along either a normal, mucosecretory, or a squamous cell pathway. Squamous differentiation in tracheobronchial epithelial cells has many morphological, biochemical, and regulatory properties in common with epidermal differentiation. This pathway of differentiation is a multistep process consisting of at least three stages. In the initial stage, cells become committed to terminal cell division. This is followed by the expression of the squamous differentiated phenotype and finally cornification. Various factors, such as several growth factors, retinoids, calcium ions, and phorbol esters, regulate the program of differentiation at different stages. Studies have indicated that the controls of proliferation and differentiation are interrelated. Cell lines established from tracheobronchial epithelial cells expressing SV40 large T-antigen, as well as carcinoma cell lines, exhibit altered responses to growth and differentiation regulatory factors Alterations in the commitment to terminal cell division must be a crucial step in the transition of a normal to a malignant cell.
The airway epithelium, which is commonly exposed to xenobiotics, contains the conjugative enzyme phenol sulfotransferase (PST). We have previously reported that hydrocortisone (HC) stimulates the expression of PST severalfold in cultured bovine bronchial epithelial cells (Beckmann et al., 1994, J. Cell. Physiol. 160:603-610). Here we report that this stimulation is attenuated by retinoic acid (RA). Dose-response measurements of both enzyme activities and mRNA levels indicated a 50% inhibition of HC-stimulated PST expression with 0.05 nM RA. Varied concentrations of RA had a general repressive effect on HC-stimulated PST expression, with no change in the half-maximal HC stimulatory concentration of 12.5 nM. Steady state kinetic measurements indicated no significant changes in apparent Km values of 3-5 microM for the acceptor substrate, 2-naphthol; only HC- and RA-dependent changes in Vmax were observed. These changes were likely due to altered enzyme expression, as evidenced by immunoblot and Northern blot hybridization analyses. Thus, the expression of PST within bronchial epithelial cells is not merely constitutive, but is subject to both positive and negative controls.
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