Potential antipsoriatic effect of chondroitin sulphate by inhibition of NF-κB and STAT3 signalling pathways

RM Andrés1,5, MC Terencio1,5, M Payá1,5, MC Montesinos1,5, P Navalón2, F Valcuende3, M Herrero4, J Vergés4. 1University of Valencia, Pharmacology Department, 46100, Spain, 2Valencia General University Hospital, Urology Department, 46014, Spain, 3Hospital La Plana, Castellón, Dermatology Department, 12540, Spain, 4Bioibérica S.A., Scientific Medical Department, 08389, Spain, 5University of Valencia, Center of Molecular Recognition and Technological Development (IDM), 46100, Spain

Chondroitin sulphate (CS) is a natural glycosaminoglycan present in the extracellular matrix surrounding cells, where it forms an essential component of proteoglycans. CS has been classified as a symptomatic slow-acting drug in osteoarthritis (OA) and a structure/disease-modifying anti-osteoarthritic drug (1). The beneficial effects of CS in patients with OA result from different effects of CS on articular tissues, primarily from the reduction of NF-κB nuclear translocation and the decrease in the production of pro-inflammatory cytokines such as IL-1β and TNF-α.

The beneficial effects elicited by CS in the treatment of OA, raises the hypothesis that CS might be effective in other chronic inflammatory processes such as psoriasis, in which a deregulation of NF-κB is a key feature (2). In this regard, there is clinical evidence that CS has a beneficial effect on psoriasis and that it may represent a therapeutic alternative for many patients (3).

In the present study, the effect of CS (CS Bio-ActiveTM, Bioibérica S.A., Barcelona, Spain) on primary human keratinocytes was assessed in vitro. After a 24 hours preincubation, CS was able to inhibit DNA binding of NF-κB in keratinocytes after 1 hour TPA (12-O-Tetradecanoylphorbol 13-acetate, 1 µg/ml) stimulation. This effect was observed at both tested concentrations: 200 and 1000 µg/ml. As a result, CS (200 μg/ml) also impaired TNFα (39.4 ± 7.18 pg/ml vs. 79.6 ± 10.3 pg/ml; p < 0.01) and IL-8 (929.6 ± 84.2 pg/ml vs. 1393.0 ± 211.5 pg/ml; p < 0.01) release after 7 hours TPA challenge. Keratinocytes were also stimulated with TNFα (10 ng/ml) for 48 hours. In these conditions, the enhancement of IL-6 (51.5 ± 5.5 pg/ml vs. 81.0 ± 6.8 pg/ml; p < 0.01) and CCL-27 (380.7 ± 75.6 pg/ml vs. 634.8 ± 52.2 pg/ml; p < 0.01) production was significantly decreased by CS in the culture supernatants.

Subsequently, primary human keratinocytes were stimulated with IL-6 (50 ng/ml) for 1 hour in order to assess the CS effect on STAT3 signalling pathway. The expression and activation of this transcription factor has been proven to be upregulated in psoriatic lesions (4). Surprisingly, after a 24 hours preincubation, CS inhibited the nuclear translocation of STAT3 as observed by immunofluorescence and western blotting of the nuclear and cytosolic extracts.

To our knowledge, this is the first time where an effect of CS in STAT3 signalling pathway has been demonstrated. Furthermore, CS has been proven to be able to impair skin inflammation by inhibiting the activation of NF-κB and the release of some of the pivotal components of the psoriatic cytokine network. Taken all together, the results presented in this study provide further evidence of the potential beneficial effect of CS in psoriasis.

1. du Souich P, Garcia A G, Verges J, et al. J Cell Mol Med 2009: 13:1451-1463.

2. Lizzul P F, Aphale A, Malaviya R, et al. J Invest Dermatol 2005: 124:1275-1283.

3. Moller I, Perez M, Monfort J, et al. Osteoarthritis Cartilage 2010: 18 Suppl 1:S32-40.

4. Sano S, Chan K S, Carbajal S, et al. Nat Med 2005: 11:43-49.