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p38 MAP Kinase Inhibition Reduces Propionibacterium acnes-Induced Inflammation in Vitro.

Li WH, Zhang L, Lyte P, Rodriguez K, Cavender D, Southall MD - Dermatol Ther (Heidelb) (2015)

Bottom Line: Furthermore, SCIO-469, a selective inhibitor of p38α, showed similar effects in cultured keratinocytes.Topical treatment of SCIO-469 inhibited the P. acnes-induced phospho-p38 and cytokine secretion in human epidermal equivalents.Johnson & Johnson.

View Article: PubMed Central - PubMed

Affiliation: Department of Skin Biology and Pharmacology, The Johnson & Johnson Skin Research Center, Johnson & Johnson Consumer and Personal Products Worldwide, Division of Johnson and Johnson Consumer Companies, Inc., 199 Grandview Road, Skillman, NJ, 08558, USA, whli@its.jnj.com.

ABSTRACT

Introduction: Propionibacterium acnes, a ubiquitous skin bacterium, stimulates keratinocytes to produce a number of proinflammatory cytokines and may contribute to inflammatory acne. The aim of the study was to investigate whether P. acnes-induced proinflammatory cytokine release is mediated by P. acnes-induced activation of p38 mitogen-activated protein kinase (p38 MAPK or p38) in human keratinocytes.

Methods: Immunohistochemistry was used to evaluate p38 phosphorylation in human skin samples with or without acne. Primary human keratinocytes and epidermal skin equivalents were exposed to viable P. acnes. Phosphorylation of MAPKs without or with p38 inhibitors was examined by Western blot and cytokine secretion was detected by Enzyme-Linked Immunosorbent Assay (ELISA).

Results: Increased levels of phospho-p38 were observed in human acne lesions, predominantly in follicular and perifollicular keratinocytes. Exposure of cultured human keratinocytes to viable P. acnes resulted in phosphorylation of multiple members of the MAPK family, including rapid and transient activation of p38 and extracellular signal-related kinase (ERK1/2) and relatively slow but sustained activation of c-Jun N-terminal kinases (JNK1/2). Viable P. acnes induced the secretion of interleukin-1α (IL-1α), tumor necrosis factor-α (TNF-α), and IL-8 from human keratinocytes. The phosphorylation of p38 (phospho-p38) and the secretion of cytokines induced by P. acnes in cultured keratinocytes were inhibited by SB203580, a p38α/β inhibitor. Furthermore, SCIO-469, a selective inhibitor of p38α, showed similar effects in cultured keratinocytes. Topical treatment of SCIO-469 inhibited the P. acnes-induced phospho-p38 and cytokine secretion in human epidermal equivalents.

Conclusion: The data demonstrate that P. acnes induces p38-dependent inflammatory responses in keratinocytes, and suggest that p38 may play an important role in the pathogenesis of inflammatory acne.

Funding: Johnson & Johnson.

No MeSH data available.


Related in: MedlinePlus

Propionibacterium acnes-induced phosphorylation of p38, but not of ERK1/2 or JNK1/2, and the cytokine release was inhibited by a p38α inhibitor, SCIO-469, in human keratinocytes. a Western blots show that SCIO-469 inhibits P. acnes-induced phospho-p38 (p-p38) dose-dependently, but not of phospho-ERK1/2 (p-ERK1/2) or phospho-JNK1/2 (p-JNK1/2). b–c SCIO-469 inhibits the secretion of TNF-α (b), IL-8 (c), and IL-1α (d). Data are expressed as mean ± SD. p < 0.05 (*), p < 0.01 (**), p < 0.005 (***). ERK extracellular signal-related kinases, JNK c-Jun N-terminal kinases, TNF tumor necrosis factor, IL interleukin, PA Propionibacterium acnes
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Fig4: Propionibacterium acnes-induced phosphorylation of p38, but not of ERK1/2 or JNK1/2, and the cytokine release was inhibited by a p38α inhibitor, SCIO-469, in human keratinocytes. a Western blots show that SCIO-469 inhibits P. acnes-induced phospho-p38 (p-p38) dose-dependently, but not of phospho-ERK1/2 (p-ERK1/2) or phospho-JNK1/2 (p-JNK1/2). b–c SCIO-469 inhibits the secretion of TNF-α (b), IL-8 (c), and IL-1α (d). Data are expressed as mean ± SD. p < 0.05 (*), p < 0.01 (**), p < 0.005 (***). ERK extracellular signal-related kinases, JNK c-Jun N-terminal kinases, TNF tumor necrosis factor, IL interleukin, PA Propionibacterium acnes

Mentions: Pretreatment of the keratinocytes with SCIO-469 inhibited P. acnes-induced phospho-p38 in a dose-dependent fashion with a 50% inhibition at 16–80 nM, and complete inhibition was observed between 0.4 and 2 μM (Fig. 4a). There was no inhibition but upregulation of P. acnes induced either phospho-ERK1/2 or phospho-JNK1/2 (Fig. 4a). Stationary-phase P. acnes stimulated the production of TNF-α (Fig. 4b, p < 0.005), IL-8 (Fig. 4c, p < 0.005), and IL-1α (Fig. 4d, p < 0.005). Pretreatment of keratinocytes with SCIO-469 dose-dependently inhibited P. acnes-induced TNF-α secretion with an IC50 of 79 nM (Fig. 4b). SCIO-469 also significantly suppressed IL-8 and IL-1α secretion (Fig. 4c, d), but the degree of suppression was less for IL-8 and IL-1α than that observed for TNF-α.Fig. 4


p38 MAP Kinase Inhibition Reduces Propionibacterium acnes-Induced Inflammation in Vitro.

Li WH, Zhang L, Lyte P, Rodriguez K, Cavender D, Southall MD - Dermatol Ther (Heidelb) (2015)

Propionibacterium acnes-induced phosphorylation of p38, but not of ERK1/2 or JNK1/2, and the cytokine release was inhibited by a p38α inhibitor, SCIO-469, in human keratinocytes. a Western blots show that SCIO-469 inhibits P. acnes-induced phospho-p38 (p-p38) dose-dependently, but not of phospho-ERK1/2 (p-ERK1/2) or phospho-JNK1/2 (p-JNK1/2). b–c SCIO-469 inhibits the secretion of TNF-α (b), IL-8 (c), and IL-1α (d). Data are expressed as mean ± SD. p < 0.05 (*), p < 0.01 (**), p < 0.005 (***). ERK extracellular signal-related kinases, JNK c-Jun N-terminal kinases, TNF tumor necrosis factor, IL interleukin, PA Propionibacterium acnes
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4374066&req=5

Fig4: Propionibacterium acnes-induced phosphorylation of p38, but not of ERK1/2 or JNK1/2, and the cytokine release was inhibited by a p38α inhibitor, SCIO-469, in human keratinocytes. a Western blots show that SCIO-469 inhibits P. acnes-induced phospho-p38 (p-p38) dose-dependently, but not of phospho-ERK1/2 (p-ERK1/2) or phospho-JNK1/2 (p-JNK1/2). b–c SCIO-469 inhibits the secretion of TNF-α (b), IL-8 (c), and IL-1α (d). Data are expressed as mean ± SD. p < 0.05 (*), p < 0.01 (**), p < 0.005 (***). ERK extracellular signal-related kinases, JNK c-Jun N-terminal kinases, TNF tumor necrosis factor, IL interleukin, PA Propionibacterium acnes
Mentions: Pretreatment of the keratinocytes with SCIO-469 inhibited P. acnes-induced phospho-p38 in a dose-dependent fashion with a 50% inhibition at 16–80 nM, and complete inhibition was observed between 0.4 and 2 μM (Fig. 4a). There was no inhibition but upregulation of P. acnes induced either phospho-ERK1/2 or phospho-JNK1/2 (Fig. 4a). Stationary-phase P. acnes stimulated the production of TNF-α (Fig. 4b, p < 0.005), IL-8 (Fig. 4c, p < 0.005), and IL-1α (Fig. 4d, p < 0.005). Pretreatment of keratinocytes with SCIO-469 dose-dependently inhibited P. acnes-induced TNF-α secretion with an IC50 of 79 nM (Fig. 4b). SCIO-469 also significantly suppressed IL-8 and IL-1α secretion (Fig. 4c, d), but the degree of suppression was less for IL-8 and IL-1α than that observed for TNF-α.Fig. 4

Bottom Line: Furthermore, SCIO-469, a selective inhibitor of p38α, showed similar effects in cultured keratinocytes.Topical treatment of SCIO-469 inhibited the P. acnes-induced phospho-p38 and cytokine secretion in human epidermal equivalents.Johnson & Johnson.

View Article: PubMed Central - PubMed

Affiliation: Department of Skin Biology and Pharmacology, The Johnson & Johnson Skin Research Center, Johnson & Johnson Consumer and Personal Products Worldwide, Division of Johnson and Johnson Consumer Companies, Inc., 199 Grandview Road, Skillman, NJ, 08558, USA, whli@its.jnj.com.

ABSTRACT

Introduction: Propionibacterium acnes, a ubiquitous skin bacterium, stimulates keratinocytes to produce a number of proinflammatory cytokines and may contribute to inflammatory acne. The aim of the study was to investigate whether P. acnes-induced proinflammatory cytokine release is mediated by P. acnes-induced activation of p38 mitogen-activated protein kinase (p38 MAPK or p38) in human keratinocytes.

Methods: Immunohistochemistry was used to evaluate p38 phosphorylation in human skin samples with or without acne. Primary human keratinocytes and epidermal skin equivalents were exposed to viable P. acnes. Phosphorylation of MAPKs without or with p38 inhibitors was examined by Western blot and cytokine secretion was detected by Enzyme-Linked Immunosorbent Assay (ELISA).

Results: Increased levels of phospho-p38 were observed in human acne lesions, predominantly in follicular and perifollicular keratinocytes. Exposure of cultured human keratinocytes to viable P. acnes resulted in phosphorylation of multiple members of the MAPK family, including rapid and transient activation of p38 and extracellular signal-related kinase (ERK1/2) and relatively slow but sustained activation of c-Jun N-terminal kinases (JNK1/2). Viable P. acnes induced the secretion of interleukin-1α (IL-1α), tumor necrosis factor-α (TNF-α), and IL-8 from human keratinocytes. The phosphorylation of p38 (phospho-p38) and the secretion of cytokines induced by P. acnes in cultured keratinocytes were inhibited by SB203580, a p38α/β inhibitor. Furthermore, SCIO-469, a selective inhibitor of p38α, showed similar effects in cultured keratinocytes. Topical treatment of SCIO-469 inhibited the P. acnes-induced phospho-p38 and cytokine secretion in human epidermal equivalents.

Conclusion: The data demonstrate that P. acnes induces p38-dependent inflammatory responses in keratinocytes, and suggest that p38 may play an important role in the pathogenesis of inflammatory acne.

Funding: Johnson & Johnson.

No MeSH data available.


Related in: MedlinePlus