Limits...
Role of Ceramide from Glycosphingolipids and Its Metabolites in Immunological and Inflammatory Responses in Humans.

Iwabuchi K, Nakayama H, Oizumi A, Suga Y, Ogawa H, Takamori K - Mediators Inflamm. (2015)

Bottom Line: These observations suggest that the very long fatty acid chains of ceramide are critical for GSL-mediated outside-in signaling.Sphingosine is another component of ceramide, with the hydrolysis of ceramide by ceramidase producing sphingosine and fatty acids.Sphingosine is phosphorylated by sphingosine kinase to sphingosine-1-phosphate, which is involved in a wide range of cellular functions, including growth, differentiation, survival, chemotaxis, angiogenesis, and embryogenesis, in various types of cells.

View Article: PubMed Central - PubMed

Affiliation: Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Tomioka Urayasu, Chiba 2790021, Japan ; Infection Control Nursing, Juntendo University Graduate School of Health Care and Nursing, Chiba 2790023, Japan ; Laboratory of Biochemistry, Juntendo University School of Health Care and Nursing, Chiba 2790023, Japan.

ABSTRACT
Glycosphingolipids (GSLs) are composed of hydrophobic ceramide and hydrophilic sugar chains. GSLs cluster to form membrane microdomains (lipid rafts) on plasma membranes, along with several kinds of transducer molecules, including Src family kinases and small G proteins. However, GSL-mediated biological functions remain unclear. Lactosylceramide (LacCer, CDw17) is highly expressed on the plasma membranes of human phagocytes and mediates several immunological and inflammatory reactions, including phagocytosis, chemotaxis, and superoxide generation. LacCer forms membrane microdomains with the Src family tyrosine kinase Lyn and the Gαi subunit of heterotrimeric G proteins. The very long fatty acids C24:0 and C24:1 are the main ceramide components of LacCer in neutrophil plasma membranes and are directly connected with the fatty acids of Lyn and Gαi. These observations suggest that the very long fatty acid chains of ceramide are critical for GSL-mediated outside-in signaling. Sphingosine is another component of ceramide, with the hydrolysis of ceramide by ceramidase producing sphingosine and fatty acids. Sphingosine is phosphorylated by sphingosine kinase to sphingosine-1-phosphate, which is involved in a wide range of cellular functions, including growth, differentiation, survival, chemotaxis, angiogenesis, and embryogenesis, in various types of cells. This review describes the role of ceramide moiety of GSLs and its metabolites in immunological and inflammatory reactions in human.

No MeSH data available.


Related in: MedlinePlus

Schematic mechanism of the production of inflammatory mediators by ceramide metabolites in human keratinocytes. PaCDase degrades ceramide into sphingosine in the stratum corneum, and sphingosine is converted to S1P by SphK of keratinocytes. S1P is then released extracellularly and binds to S1P receptors, resulting in the production and release of TNF-α. The released TNF-α binds to TNF-α receptors, activating NF-κB and inducing the production of IL-8 and endothelin-1.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4644562&req=5

fig3: Schematic mechanism of the production of inflammatory mediators by ceramide metabolites in human keratinocytes. PaCDase degrades ceramide into sphingosine in the stratum corneum, and sphingosine is converted to S1P by SphK of keratinocytes. S1P is then released extracellularly and binds to S1P receptors, resulting in the production and release of TNF-α. The released TNF-α binds to TNF-α receptors, activating NF-κB and inducing the production of IL-8 and endothelin-1.

Mentions: A neutral CDase from Pseudomonas aeruginosa AN17 (PaCDase) isolated from a patient with atopic dermatitis (AD) was shown to require detergents to hydrolyze ceramide [53]. Staphylococcus aureus-derived lipids, which consist primarily of cardiolipin and phosphatidylglycerol, enhanced the PaCDase hydrolysis of normal ceramide and of human skin-specific omega-hydroxyacyl ceramide in the absence of detergents [11]. A three-dimensionally cultured human primary keratinocyte (3D keratinocyte) culture system has been utilized to simulate epidermal differentiation at its air-liquid interface, resulting in the generation of basal, spinous, and granular layers and an SC, with the latter displaying permeability barrier functions [54]. Treatment of 3D keratinocytes with PaCDase and water-soluble stimulants of keratinocytes, including trypsin, Dermatophagoides pteronyssinus class 1 allergen (Der p1), and Dermatophagoides farinae allergen (Der f1) had no effect on the expression of any of the genes in our DNA microarray analysis [55], indicating that the SC of the 3D keratinocyte culture acts as a permeability barrier. Triton X-100 is a detergent that reduces permeability barrier functions, thereby moderately increasing transepidermal water loss and the production of erythema on human skin [56]. In the presence of 0.1% Triton X-100, PaCDase markedly enhanced TNF-α mRNA expression in 3D keratinocytes, an increase not observed in cells treated with Triton X-100 alone [55]. TNF-α mRNA expression was not enhanced by heat-inactivated or mutant PaCDase, suggesting that ceramide metabolites induce TNF-α mRNA expression in keratinocytes. TNF-α, a critical cytokine in several dermatological diseases [57], is secreted by keratinocytes [58] and shown to be involved in the progression of atopic dermatitis (AD) [59]. Among the metabolites of ceramide, only sphingosine and S1P enhanced TNF-α mRNA levels in 3D keratinocytes. S1P is synthesized from sphingosine by sphingosine kinase (SphK) and stimulates 3D keratinocytes through specific receptors [60]. Both the specific SphK inhibitor CAS 1177741-83-1 and the S1P receptor antagonist VPC 23019 suppressed the PaCDase-induced expression of TNF-α mRNA in 3D keratinocytes. S1P is generally considered to stimulate cells through plasma membrane G protein-coupled receptors, for example, S1P1–S1P5 [61]. S1P was recently shown to activate NF-κB [62] independently of S1P receptors [63]. However, VPC2301, a competitive antagonist for S1P1 and S1P3 receptors, inhibited the PaCDase-enhanced gene expression not only of TNF-α but also of endothelin-1 and IL-8 [55]. Thus, the S1P-induced production of these inflammatory mediators is mediated by S1P receptors in human primary keratinocytes in a 3D culture system. cDNA microarray analysis showed that S1P strongly upregulated the expression of endothelin-1, CXCL1, TNF-α, β-defensin 5, IL-8, CXCL2, interferon regulatory factor 1, GADD45 gamma, and IL-23α subunit mRNAs [55]. IL-8, CXCL1, and CXCL2 have been reported to be upregulated in the lesional skin of patients with AD and psoriasis [64]. S1P also enhanced the expression of claudin-4 mRNA, which has been observed in more layers of psoriatic than normal epidermis [65]. TNF-α can induce the production of endothelin-1 and IL-8 by human keratinocytes [66, 67]. Epidermal keratinocytes produce and respond to TNF-α via TNFR1 [68]. Infliximab, a chimeric IgG1κ monoclonal antibody against human TNF-α, inhibits the TNF-α-mediated production of IL-8 by keratinocytes [69]. PaCDase-induced phosphorylation of NF-κB p65 was markedly suppressed by infliximab [55]. The NF-κB inhibitor curcumin inhibited PaCDase-induced expression of IL-8 and endothelin-1 mRNAs but not of TNF-α mRNA. TNF-α induces IL-8 production via NF-κB [70]. Therefore, it is likely that S1P induces TNF-α production and release from 3D keratinocytes via S1P receptors, resulting in TNF-α induction of cytokine production through NF-κB-mediated signal transduction (Figure 3). TNF-α is a critical cytokine in psoriatic immunopathology, and the development of an effective strategy is required to counteract its effects [57]. Infliximab, which is used to treat patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis (excluding localized type), and psoriatic erythroderma [71, 72], downregulates antiapoptotic proteins in regressing psoriatic skin [72]. The effects of infliximab have also been evaluated in other inflammatory dermatoses and in systemic diseases involving the skin, pityriasis rubra pilaris, pyoderma gangrenosum, and cutaneous sarcoidosis [73]. AD is characterized by a marked reduction in ceramides in the SC of lesional and nonlesional forearms [74, 75] and by increased activities of the enzymes ceramidase (CDase). The metabolic conversion of ceramide to S1P has been found to protect keratinocytes against UVB-induced, ceramide-mediated apoptosis [76]. These observations suggest that ceramide metabolites, especially S1P, are involved in AD. AD is a common pruritic, inflammatory skin disorder [77]. Chronic, localized, or even generalized pruritus is the diagnostic hallmark of AD. Histamine H1-receptor blockers are used to treat all types of itch resulting from serious skin diseases, such as AD, as well as from renal and liver diseases. However, they often lack efficacy in chronic itch, a profound clinical problem that decreases quality of life [78]. Nerve density in the epidermis is partly involved in itch sensitization in pruritic skin diseases, such as AD [79]. Endothelin-1 has been shown to elicit itch in humans [80–82]. The molecular pathways that contribute to the transduction of itch responses to endothelin-1 do not require either PLCβ3 or TRPV1 of neurons, which mediate histamine- and serotonin-induced itch responses, respectively [83]. Thus, keratinocyte-produced S1P may be involved in endothelin-1-mediated pruritus in AD. Therefore, atopic dermatitis may be exacerbated by treatment with S1P analogue FTY720.


Role of Ceramide from Glycosphingolipids and Its Metabolites in Immunological and Inflammatory Responses in Humans.

Iwabuchi K, Nakayama H, Oizumi A, Suga Y, Ogawa H, Takamori K - Mediators Inflamm. (2015)

Schematic mechanism of the production of inflammatory mediators by ceramide metabolites in human keratinocytes. PaCDase degrades ceramide into sphingosine in the stratum corneum, and sphingosine is converted to S1P by SphK of keratinocytes. S1P is then released extracellularly and binds to S1P receptors, resulting in the production and release of TNF-α. The released TNF-α binds to TNF-α receptors, activating NF-κB and inducing the production of IL-8 and endothelin-1.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4644562&req=5

fig3: Schematic mechanism of the production of inflammatory mediators by ceramide metabolites in human keratinocytes. PaCDase degrades ceramide into sphingosine in the stratum corneum, and sphingosine is converted to S1P by SphK of keratinocytes. S1P is then released extracellularly and binds to S1P receptors, resulting in the production and release of TNF-α. The released TNF-α binds to TNF-α receptors, activating NF-κB and inducing the production of IL-8 and endothelin-1.
Mentions: A neutral CDase from Pseudomonas aeruginosa AN17 (PaCDase) isolated from a patient with atopic dermatitis (AD) was shown to require detergents to hydrolyze ceramide [53]. Staphylococcus aureus-derived lipids, which consist primarily of cardiolipin and phosphatidylglycerol, enhanced the PaCDase hydrolysis of normal ceramide and of human skin-specific omega-hydroxyacyl ceramide in the absence of detergents [11]. A three-dimensionally cultured human primary keratinocyte (3D keratinocyte) culture system has been utilized to simulate epidermal differentiation at its air-liquid interface, resulting in the generation of basal, spinous, and granular layers and an SC, with the latter displaying permeability barrier functions [54]. Treatment of 3D keratinocytes with PaCDase and water-soluble stimulants of keratinocytes, including trypsin, Dermatophagoides pteronyssinus class 1 allergen (Der p1), and Dermatophagoides farinae allergen (Der f1) had no effect on the expression of any of the genes in our DNA microarray analysis [55], indicating that the SC of the 3D keratinocyte culture acts as a permeability barrier. Triton X-100 is a detergent that reduces permeability barrier functions, thereby moderately increasing transepidermal water loss and the production of erythema on human skin [56]. In the presence of 0.1% Triton X-100, PaCDase markedly enhanced TNF-α mRNA expression in 3D keratinocytes, an increase not observed in cells treated with Triton X-100 alone [55]. TNF-α mRNA expression was not enhanced by heat-inactivated or mutant PaCDase, suggesting that ceramide metabolites induce TNF-α mRNA expression in keratinocytes. TNF-α, a critical cytokine in several dermatological diseases [57], is secreted by keratinocytes [58] and shown to be involved in the progression of atopic dermatitis (AD) [59]. Among the metabolites of ceramide, only sphingosine and S1P enhanced TNF-α mRNA levels in 3D keratinocytes. S1P is synthesized from sphingosine by sphingosine kinase (SphK) and stimulates 3D keratinocytes through specific receptors [60]. Both the specific SphK inhibitor CAS 1177741-83-1 and the S1P receptor antagonist VPC 23019 suppressed the PaCDase-induced expression of TNF-α mRNA in 3D keratinocytes. S1P is generally considered to stimulate cells through plasma membrane G protein-coupled receptors, for example, S1P1–S1P5 [61]. S1P was recently shown to activate NF-κB [62] independently of S1P receptors [63]. However, VPC2301, a competitive antagonist for S1P1 and S1P3 receptors, inhibited the PaCDase-enhanced gene expression not only of TNF-α but also of endothelin-1 and IL-8 [55]. Thus, the S1P-induced production of these inflammatory mediators is mediated by S1P receptors in human primary keratinocytes in a 3D culture system. cDNA microarray analysis showed that S1P strongly upregulated the expression of endothelin-1, CXCL1, TNF-α, β-defensin 5, IL-8, CXCL2, interferon regulatory factor 1, GADD45 gamma, and IL-23α subunit mRNAs [55]. IL-8, CXCL1, and CXCL2 have been reported to be upregulated in the lesional skin of patients with AD and psoriasis [64]. S1P also enhanced the expression of claudin-4 mRNA, which has been observed in more layers of psoriatic than normal epidermis [65]. TNF-α can induce the production of endothelin-1 and IL-8 by human keratinocytes [66, 67]. Epidermal keratinocytes produce and respond to TNF-α via TNFR1 [68]. Infliximab, a chimeric IgG1κ monoclonal antibody against human TNF-α, inhibits the TNF-α-mediated production of IL-8 by keratinocytes [69]. PaCDase-induced phosphorylation of NF-κB p65 was markedly suppressed by infliximab [55]. The NF-κB inhibitor curcumin inhibited PaCDase-induced expression of IL-8 and endothelin-1 mRNAs but not of TNF-α mRNA. TNF-α induces IL-8 production via NF-κB [70]. Therefore, it is likely that S1P induces TNF-α production and release from 3D keratinocytes via S1P receptors, resulting in TNF-α induction of cytokine production through NF-κB-mediated signal transduction (Figure 3). TNF-α is a critical cytokine in psoriatic immunopathology, and the development of an effective strategy is required to counteract its effects [57]. Infliximab, which is used to treat patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis (excluding localized type), and psoriatic erythroderma [71, 72], downregulates antiapoptotic proteins in regressing psoriatic skin [72]. The effects of infliximab have also been evaluated in other inflammatory dermatoses and in systemic diseases involving the skin, pityriasis rubra pilaris, pyoderma gangrenosum, and cutaneous sarcoidosis [73]. AD is characterized by a marked reduction in ceramides in the SC of lesional and nonlesional forearms [74, 75] and by increased activities of the enzymes ceramidase (CDase). The metabolic conversion of ceramide to S1P has been found to protect keratinocytes against UVB-induced, ceramide-mediated apoptosis [76]. These observations suggest that ceramide metabolites, especially S1P, are involved in AD. AD is a common pruritic, inflammatory skin disorder [77]. Chronic, localized, or even generalized pruritus is the diagnostic hallmark of AD. Histamine H1-receptor blockers are used to treat all types of itch resulting from serious skin diseases, such as AD, as well as from renal and liver diseases. However, they often lack efficacy in chronic itch, a profound clinical problem that decreases quality of life [78]. Nerve density in the epidermis is partly involved in itch sensitization in pruritic skin diseases, such as AD [79]. Endothelin-1 has been shown to elicit itch in humans [80–82]. The molecular pathways that contribute to the transduction of itch responses to endothelin-1 do not require either PLCβ3 or TRPV1 of neurons, which mediate histamine- and serotonin-induced itch responses, respectively [83]. Thus, keratinocyte-produced S1P may be involved in endothelin-1-mediated pruritus in AD. Therefore, atopic dermatitis may be exacerbated by treatment with S1P analogue FTY720.

Bottom Line: These observations suggest that the very long fatty acid chains of ceramide are critical for GSL-mediated outside-in signaling.Sphingosine is another component of ceramide, with the hydrolysis of ceramide by ceramidase producing sphingosine and fatty acids.Sphingosine is phosphorylated by sphingosine kinase to sphingosine-1-phosphate, which is involved in a wide range of cellular functions, including growth, differentiation, survival, chemotaxis, angiogenesis, and embryogenesis, in various types of cells.

View Article: PubMed Central - PubMed

Affiliation: Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Tomioka Urayasu, Chiba 2790021, Japan ; Infection Control Nursing, Juntendo University Graduate School of Health Care and Nursing, Chiba 2790023, Japan ; Laboratory of Biochemistry, Juntendo University School of Health Care and Nursing, Chiba 2790023, Japan.

ABSTRACT
Glycosphingolipids (GSLs) are composed of hydrophobic ceramide and hydrophilic sugar chains. GSLs cluster to form membrane microdomains (lipid rafts) on plasma membranes, along with several kinds of transducer molecules, including Src family kinases and small G proteins. However, GSL-mediated biological functions remain unclear. Lactosylceramide (LacCer, CDw17) is highly expressed on the plasma membranes of human phagocytes and mediates several immunological and inflammatory reactions, including phagocytosis, chemotaxis, and superoxide generation. LacCer forms membrane microdomains with the Src family tyrosine kinase Lyn and the Gαi subunit of heterotrimeric G proteins. The very long fatty acids C24:0 and C24:1 are the main ceramide components of LacCer in neutrophil plasma membranes and are directly connected with the fatty acids of Lyn and Gαi. These observations suggest that the very long fatty acid chains of ceramide are critical for GSL-mediated outside-in signaling. Sphingosine is another component of ceramide, with the hydrolysis of ceramide by ceramidase producing sphingosine and fatty acids. Sphingosine is phosphorylated by sphingosine kinase to sphingosine-1-phosphate, which is involved in a wide range of cellular functions, including growth, differentiation, survival, chemotaxis, angiogenesis, and embryogenesis, in various types of cells. This review describes the role of ceramide moiety of GSLs and its metabolites in immunological and inflammatory reactions in human.

No MeSH data available.


Related in: MedlinePlus