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

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. acnesinduced proinflammatory cytokine release is mediated by P. acnes-induced activation of p38mitogen-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-1a (IL-1a), tumor necrosis factor-a (TNF-a), 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 p38a/b inhibitor. Furthermore, SCIO-469, a selective inhibitor of p38a, 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.

EpiDerm (EPI-200), Propionibacterium acnes strain ATCC 11828, phospho-p38, p38 inhibitors, extracellular signal-related kinase (ERK1/2), c-Jun N-terminal kinases, JNK1/2, TNF-a, IL-8, SCIO-469

Propionibacterium acnes, p38 inhibitors, SCIO-469