Limits...
IL-22/STAT3-Induced Increases in SLURP1 Expression within Psoriatic Lesions Exerts Antimicrobial Effects against Staphylococcus aureus.

Moriwaki Y, Takada K, Nagasaki T, Kubo N, Ishii T, Kose K, Kageyama T, Tsuji S, Kawashima K, Misawa H - PLoS ONE (2015)

Bottom Line: In NHEKs stimulated with the inflammatory cytokines IL-17, IL-22 and TNF-α, which are reportedly expressed in psoriatic lesions, SLURP1 mRNA expression was significantly up-regulated by IL-22 but not the other two cytokines.The stimulatory effect of IL-22 was completely suppressed in NHEKs treated with a STAT3 inhibitor or transfected with siRNA targeting STAT3.SLURP1 significantly suppressed the growth of S. aureus.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo 105-8512, Japan.

ABSTRACT

Background: SLURP1 is the causal gene for Mal de Meleda (MDM), an autosomal recessive skin disorder characterized by diffuse palmoplantar keratoderma and transgressive keratosis. Moreover, although SLURP1 likely serves as an important proliferation/differentiation factor in keratinocytes, the possible relation between SLURP1 and other skin diseases, such as psoriasis and atopic dermatitis, has not been studied, and the pathophysiological control of SLURP1 expression in keratinocytes is largely unknown.

Objectives: Our aim was to examine the involvement of SLURP1 in the pathophysiology of psoriasis using an imiquimod (IMQ)-induced psoriasis model mice and normal human epidermal keratinocytes (NHEKs).

Results: SLURP1 expression was up-regulated in the skin of IMQ-induced psoriasis model mice. In NHEKs stimulated with the inflammatory cytokines IL-17, IL-22 and TNF-α, which are reportedly expressed in psoriatic lesions, SLURP1 mRNA expression was significantly up-regulated by IL-22 but not the other two cytokines. The stimulatory effect of IL-22 was completely suppressed in NHEKs treated with a STAT3 inhibitor or transfected with siRNA targeting STAT3. Because IL-22 induces production of antimicrobial proteins in epithelial cells, the antibacterial activity of SLURP1 was assessed against Staphylococcus aureus (S. aureus), which is known to be associated with disease severity in psoriasis. SLURP1 significantly suppressed the growth of S. aureus.

Conclusions: These results indicate SLURP1 participates in pathophysiology of psoriasis by regulating keratinocyte proliferation and differentiation, and by suppressing the growth of S. aureus.

No MeSH data available.


Related in: MedlinePlus

SLURP1 expression is directly and transcriptionally regulated through IL-22.(A, B) NHEKs were stimulated 24 h with the indicated panel of cytokines (50 ng/ml) (A) or with 0.5, 5, 50, 500 and 1000 ng/ml IL-22 (B), after which SLURP1 mRNA levels were measured using quantitative real-time PCR. (C) NHEKs were stimulated with IL-22 or left untreated for 24 h in the presence of actinomycin D (Act. D), cycloheximide (CHX) or the control solvent (DMSO), after which SLURP1 expression was analyzed using real-time PCR. (D, E) NHEKs were stimulated for 24 h with IL-22 or a combination of IL-22 plus IL-17A, TNF-α or IFN-γ. SLURP1 expression was then analyzed using real-time PCR (D) and western blotting (E). Bars depict the mean ± S.D. (n = 6). *p < 0.05, ***p < 0.001 (one-way ANOVA).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4608685&req=5

pone.0140750.g002: SLURP1 expression is directly and transcriptionally regulated through IL-22.(A, B) NHEKs were stimulated 24 h with the indicated panel of cytokines (50 ng/ml) (A) or with 0.5, 5, 50, 500 and 1000 ng/ml IL-22 (B), after which SLURP1 mRNA levels were measured using quantitative real-time PCR. (C) NHEKs were stimulated with IL-22 or left untreated for 24 h in the presence of actinomycin D (Act. D), cycloheximide (CHX) or the control solvent (DMSO), after which SLURP1 expression was analyzed using real-time PCR. (D, E) NHEKs were stimulated for 24 h with IL-22 or a combination of IL-22 plus IL-17A, TNF-α or IFN-γ. SLURP1 expression was then analyzed using real-time PCR (D) and western blotting (E). Bars depict the mean ± S.D. (n = 6). *p < 0.05, ***p < 0.001 (one-way ANOVA).

Mentions: Several inflammatory cytokines, including IL-1β, IL-17A, IL-22 and TNF-α, are reportedly up-regulated in psoriatic lesions [2–4]. To identify endogenous factors involved in the regulation of SLURP1 gene expression, NHEKs were stimulated using the panel of cytokines shown in Fig 2A. Expression of SLURP1 mRNA was enhanced by IL-22, but not IL-1β, IL-17A, IFN-γ or TNF-α. Moreover, the stimulatory effect of IL-22 was dose-dependent (Fig 2B) and was inhibited by simultaneous addition of actinomycin D, but not by cycloheximide (Fig 2C). Expression of SLURP1 was enhanced by 50 ng/mL IL-22, and the protein was detected as a secreted form in the culture supernatant (Fig 2D). Taken together, these results suggest that SLURP1 is a direct target of IL-22 and that the increase in SLURP1 protein expression was transcriptionally regulated.


IL-22/STAT3-Induced Increases in SLURP1 Expression within Psoriatic Lesions Exerts Antimicrobial Effects against Staphylococcus aureus.

Moriwaki Y, Takada K, Nagasaki T, Kubo N, Ishii T, Kose K, Kageyama T, Tsuji S, Kawashima K, Misawa H - PLoS ONE (2015)

SLURP1 expression is directly and transcriptionally regulated through IL-22.(A, B) NHEKs were stimulated 24 h with the indicated panel of cytokines (50 ng/ml) (A) or with 0.5, 5, 50, 500 and 1000 ng/ml IL-22 (B), after which SLURP1 mRNA levels were measured using quantitative real-time PCR. (C) NHEKs were stimulated with IL-22 or left untreated for 24 h in the presence of actinomycin D (Act. D), cycloheximide (CHX) or the control solvent (DMSO), after which SLURP1 expression was analyzed using real-time PCR. (D, E) NHEKs were stimulated for 24 h with IL-22 or a combination of IL-22 plus IL-17A, TNF-α or IFN-γ. SLURP1 expression was then analyzed using real-time PCR (D) and western blotting (E). Bars depict the mean ± S.D. (n = 6). *p < 0.05, ***p < 0.001 (one-way ANOVA).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608685&req=5

pone.0140750.g002: SLURP1 expression is directly and transcriptionally regulated through IL-22.(A, B) NHEKs were stimulated 24 h with the indicated panel of cytokines (50 ng/ml) (A) or with 0.5, 5, 50, 500 and 1000 ng/ml IL-22 (B), after which SLURP1 mRNA levels were measured using quantitative real-time PCR. (C) NHEKs were stimulated with IL-22 or left untreated for 24 h in the presence of actinomycin D (Act. D), cycloheximide (CHX) or the control solvent (DMSO), after which SLURP1 expression was analyzed using real-time PCR. (D, E) NHEKs were stimulated for 24 h with IL-22 or a combination of IL-22 plus IL-17A, TNF-α or IFN-γ. SLURP1 expression was then analyzed using real-time PCR (D) and western blotting (E). Bars depict the mean ± S.D. (n = 6). *p < 0.05, ***p < 0.001 (one-way ANOVA).
Mentions: Several inflammatory cytokines, including IL-1β, IL-17A, IL-22 and TNF-α, are reportedly up-regulated in psoriatic lesions [2–4]. To identify endogenous factors involved in the regulation of SLURP1 gene expression, NHEKs were stimulated using the panel of cytokines shown in Fig 2A. Expression of SLURP1 mRNA was enhanced by IL-22, but not IL-1β, IL-17A, IFN-γ or TNF-α. Moreover, the stimulatory effect of IL-22 was dose-dependent (Fig 2B) and was inhibited by simultaneous addition of actinomycin D, but not by cycloheximide (Fig 2C). Expression of SLURP1 was enhanced by 50 ng/mL IL-22, and the protein was detected as a secreted form in the culture supernatant (Fig 2D). Taken together, these results suggest that SLURP1 is a direct target of IL-22 and that the increase in SLURP1 protein expression was transcriptionally regulated.

Bottom Line: In NHEKs stimulated with the inflammatory cytokines IL-17, IL-22 and TNF-α, which are reportedly expressed in psoriatic lesions, SLURP1 mRNA expression was significantly up-regulated by IL-22 but not the other two cytokines.The stimulatory effect of IL-22 was completely suppressed in NHEKs treated with a STAT3 inhibitor or transfected with siRNA targeting STAT3.SLURP1 significantly suppressed the growth of S. aureus.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo 105-8512, Japan.

ABSTRACT

Background: SLURP1 is the causal gene for Mal de Meleda (MDM), an autosomal recessive skin disorder characterized by diffuse palmoplantar keratoderma and transgressive keratosis. Moreover, although SLURP1 likely serves as an important proliferation/differentiation factor in keratinocytes, the possible relation between SLURP1 and other skin diseases, such as psoriasis and atopic dermatitis, has not been studied, and the pathophysiological control of SLURP1 expression in keratinocytes is largely unknown.

Objectives: Our aim was to examine the involvement of SLURP1 in the pathophysiology of psoriasis using an imiquimod (IMQ)-induced psoriasis model mice and normal human epidermal keratinocytes (NHEKs).

Results: SLURP1 expression was up-regulated in the skin of IMQ-induced psoriasis model mice. In NHEKs stimulated with the inflammatory cytokines IL-17, IL-22 and TNF-α, which are reportedly expressed in psoriatic lesions, SLURP1 mRNA expression was significantly up-regulated by IL-22 but not the other two cytokines. The stimulatory effect of IL-22 was completely suppressed in NHEKs treated with a STAT3 inhibitor or transfected with siRNA targeting STAT3. Because IL-22 induces production of antimicrobial proteins in epithelial cells, the antibacterial activity of SLURP1 was assessed against Staphylococcus aureus (S. aureus), which is known to be associated with disease severity in psoriasis. SLURP1 significantly suppressed the growth of S. aureus.

Conclusions: These results indicate SLURP1 participates in pathophysiology of psoriasis by regulating keratinocyte proliferation and differentiation, and by suppressing the growth of S. aureus.

No MeSH data available.


Related in: MedlinePlus