Kojic acid-induced IL-6 production in human keratinocytes plays a role in its anti-melanogenic activity in skin

J Dermatol Sci. 2012 Jun;66(3):207-15. doi: 10.1016/j.jdermsci.2012.03.002. Epub 2012 Mar 14.


Background: Kojic acid is a fungal metabolite widely used in medicinal and cosmetic formulations as a skin-lightening agent based on its de-pigmenting activity. Although in human clinical studies kojic acid has been shown to be effective in the treatment of hyper-pigmentation disorders such as melasma, the reasons for its apparent lack of anti-melanogenic activity in cultured mammalian melanocytes are unclear.

Objectives: This study was aimed to elucidate pharmacological mechanisms of the in vivo anti-melanogenic activity of kojic acid in human skin.

Methods: A primary human melanocyte and keratinocyte co-culture system was used to evaluate whether kojic-acid-induced changes in keratinocytes were associated with anti-melanogenic activities in melanocytes. The cytokine secretion profiles in response to kojic acid were analyzed.

Results: Kojic acid increased interleukin (IL)-6 and IL-8 production in melanocyte/keratinocyte co-cultures; however, IL-6 directly inhibited melanogenesis whereas IL-8 did not. In melanocyte monocultures, kojic acid did not increase IL-6 production whereas in keratinocyte monocultures it significantly up-regulated IL-6 gene and protein expression. Therefore, the up-regulation of IL-6 in melanocyte/keratinocyte co-cultures seems to be originated from kojic acid-induced changes in keratinocytes. Anti-IL-6 antibody treatment antagonized the anti-melanogenic effect of kojic acid on the co-cultures.

Conclusions: The pharmacological mechanism of kojic acid to explain clinically effective anti-melanogenic activity on hyper-pigmented skin is associated with the kojic acid-induced IL-6 production in keratinocytes. The cross-talk between melanocytes and keratinocytes should be determined in future studies on the pharmacological mechanisms of clinically effective dermatological drugs acting on the epidermis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Communication
  • Cell Survival
  • Coculture Techniques
  • Humans
  • Interleukin-6 / metabolism*
  • Interleukin-8 / metabolism
  • Keratinocytes / cytology
  • Keratinocytes / drug effects*
  • Keratinocytes / metabolism*
  • Melanins / metabolism*
  • Melanocytes / cytology
  • Melanocytes / drug effects*
  • Melanocytes / metabolism*
  • Monophenol Monooxygenase / metabolism
  • Pigmentation
  • Pyrones / pharmacology*
  • Skin / cytology
  • Skin / drug effects
  • Skin / metabolism*
  • Up-Regulation


  • Interleukin-6
  • Interleukin-8
  • Melanins
  • Pyrones
  • kojic acid
  • Monophenol Monooxygenase