The selective serotonin reuptake inhibitor fluoxetine exerts anti-inflammatory actions on human epidermal keratinocytes

Kinga Fanni Tóth1, Judit Szabó-Papp1, Ana Kilic2, Michael Soeberdt2, Christoph Abels2, Tamás Bíró3, Attila Oláh1

1Department of Physiology, University of Debrecen, Debrecen, Hungary; 2Dr. August Wolff GmbH & Co. KG Arzneimittel, Bielefeld, Germany; 3Department of Immunology, University of Debrecen, Debrecen, Hungary

By releasing several cytokines and mediators (e.g. endothelin 1 [ET1]), keratinocytes are key players in orchestrating cutaneous inflammation and itch. The selective serotonin reuptake inhibitor (SSRI) fluoxetine (FX), a widely applied antidepressant, has already been shown to exert anti-inflammatory actions in mice; thus, in the current study, we assessed putative anti-inflammatory effects of selected SSRIs (FX, citalopram [CP] and paroxetine [PX]) as well as serotonin (5HT) on immortalized (HaCaT) and primary (NHEK) human epidermal keratinocytes.

We found that, although high (>10 μM) concentrations of FX and PX (but not CP or 5HT) decreased viability (48-72h), non-cytotoxic doses of FX and PX (but again, not CP or 5HT) suppressed poly-(I:C)-induced elevation of the production of several pro-inflammatory cytokines (HaCaT; Q-PCR and ELISA). Moreover, FX (but not 5HT) prevented poly-(I:C)-induced ET1 release (HaCaT; ELISA), exerted anti-proliferative actions (HaCaT; CyQUANT assay), and prevented confluence and high extracellular Ca2+ concentration-induced up-regulation of several differentiation markers (HaCaT and NHEK; Q-PCR); however the latter effect exhibited great donor dependence at the protein level (NHEK; Western blot). Finally, we found that both FX and 5HT inhibited poly-(I:C)-induced activation of p38 MAPK, but had no effect on the NF-κB pathway (HaCaT; Western blot), and our preliminary data suggest that FX (but not 5HT) may induce Ca2+-influx to the keratinocytes (HaCaT; Fluo-4 AM).

Collectively, FX exerted anti-inflammatory effects, and suppressed the release of ET1 of the keratinocytes in a most probably 5HT receptor independent way. Considering its excellent safety profile, these data may encourage one to test efficiency of its topical formulations in alleviating cutaneous inflammation and itch in appropriate clinical trials.