Alpha‐Melanocyte‐Stimulating Hormone Modulates Activation of NF‐κB and AP‐1 and Secretion of Interleukin‐8 in Human Dermal Fibroblasts

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Abstract
Alpha-melanocyte-stimulating hormone (α-MSH) has evolved as a mediator of diverse biological activities in an ever-growing number of non-melanocytic cell types. One mechanism by which α-MSH exerts its effects is modulation of AP-1 and NF-κB. These two transcription factors also play an important role in fibroblasts, in extracellular matrix composition, and in cytokine expression. By use of electric mobility shift assays, we demonstrate that α-MSH (10−6 to 10−14 M) activates AP-1 in human dermal fibroblasts, whereas coincubation with interleukin-1β (IL-1β) results in suppression of its activation. α-MSH also induces activation of NF-κB but does not modulate DNA binding on costimulation with IL-1β. Since AP-1 and NF-κB are key elements in controlling interleukin-8 (IL-8) transcription, human fibroblasts were treated with α-MSH and IL-1β for 24 hours, and cytokine levels in the supernatants were measured by ELISA. α-MSH alone had little effect, whereas coincubation with IL-1β led to marked downregulation of IL-8 secretion (at most 288 ± 152 ng/mL) when compared to treatment with IL-1β alone (919 ± 157 ng/mL). Our results indicate that α-MSH exerts modulatory effects on the activation of NF-κB and AP-1, and that it can regulate chemokine secretion in human dermal fibroblasts. These effects of α-MSH may have important regulatory functions in extracellular matrix composition, wound healing, or angiogenesis.