Luteolin Prevents Solar Radiation-Induced Matrix Metalloproteinase-1 Activation in Human Fibroblasts: A Role for p38 Mitogen-Activated Protein Kinase and Interleukin-20 Released from Keratinocytes

Abstract

Human skin is continuously exposed to solar radiation, which can result in photoaging, a process involving both dermal and, to a lesser extent, epidermal structures. Previously, we have shown that the flavonoid luteolin protects the epidermis from ultraviolet (UV)-induced damage by a combination of UV-absorbing, antioxidant, and antiinflammatory properties. The aim of the present study was to determine direct and indirect effects of luteolin on dermal fibroblasts as major targets of photoaging. Stimulation of fibroblasts with UVA light or the proinflammatory cytokine interleukin-20 (IL-20) is associated with wrinkled skin, increased IL-6 secretion, matrix metalloproteinase (MMP-1) expression, and hyaluronidase activity. All of these targets were inhibited by luteolin via interference with the p38 mitogen-activated protein kinase (MAPK) pathway. Next, we assessed the role of conditioned supernatants from keratinocytes irradiated with solar-simulated radiation (SSR) on nonirradiated dermal fibroblasts. In keratinocytes, luteolin inhibited SSR-induced production of IL-20, also via interference with the p38 MAPK pathway. Similarly, keratinocyte supernatant-induced IL-6 and MMP-1 expression in fibroblasts was reduced by pretreatment of keratinocytes with luteolin. Finally, these results were confirmed ex vivo on skin explants treated with luteolin before UV irradiation. Our results suggest that SSRmediated production of soluble factors in keratinocytes is modulated by luteolin and may attenuate photoaging in dermal fibroblasts.

Luteolin Suppresses Ultraviolet A- and B-induced Matrix Metalloproteinase 1- and 9 Expression in Human Dermal Fibroblast Cells

“…Human dermal fibroblast cells exposed to UVA (6.3 J/cm 2 ) induced MMP-1 when luteolin was inoculated into the cell culture at 1-10 µM, reducing the expression of MMP-1 protein and mRNA [31]. Another study by Wölfle et al showed that luteolin at 4 µg/mL inhibits MMP-1 expression against UVA-1 (20 J/cm 2 )-induced human dermal fibroblast cells [32].…”

“…However, a few studies have investigated the direct modulatory effects of luteolin on MMPs during photoaging [29][30][31][32][33]. Moreover, to date, a relationship between luteolin and MMP-9 against both UVA and UVB-irradiation has not been demonstrated, despite the importance of MMP-9 and collagen breakdown during photoaging using HDF cells [19].…”

New Herbal Biomedicines for the Topical Treatment of Dermatological Disorders

“…It has been shown that Dyer's weed extracts and luteolin display prominent anti-oxidant and anti-inflammatory effects in skin cells [58]. Additionally, luteolin absorbs UVA radiation and protects skin cells from UVB-induced DNA -damage [59,60]. In a randomized, placebo-controlled, double-blind study with 40 healthy volunteers a Dyer's weed extract containing 2.5% luteolin reduced UVB-induced erythema to a similar extent as 1% hydrocortisone [61] (LOE-A).…”

Phytochemicals for the Prevention of Photocarcinogenesis

“…Similar effects were observed when UVA‐exposed dermal fibroblasts were treated with luteolin. By inhibiting the MAPK pathway, luteolin decreased UVA‐induced MMP‐1 expression, which may suggest the protective effects of luteolin . Because MMPs play a role in degradation of ECM, angiogenesis and tumor invasion, luteolin may be used as a protective agent against photocarcinogenesis .…”

“…Luteolin is a flavonoid found in onions, broccoli, chili, carrot and celery which exhibits anticarcinogenic and anti-inflammatory effects (165,(188)(189)(190)(191). Studies using HaCaT cells found that luteolin inhibits UVA-induced AP-1 activation as well as c-Fos, c-Jun and MMP-1 expressions (165).…”