Interleukin-17 and tumor necrosis factor show a functional hierarchy to regulate the production of matrix metalloproteases by monocytes from patients with psoriasis

Abstract Interleukin-17 (IL-17) and tumor necrosis factor (TNF) regulate the remodeling of the extracellular matrix by endopeptidases. However, it is not yet clear whether these cytokines have a functional hierarchy. This study aimed to assess whether IL-17 and TNF are hierarchically structured in psoriasis. Monocytes from 60 patients with plaque psoriasis and 60 non-psoriatic controls were stimulated in vitro with IL-17 or TNF, and the production of matrix metalloproteinases (MMPs) and their inhibitor (TIMP-1) were measured. Serum levels of inflammatory mediators also were measured. Serum levels of TNF, IL-17, MMP-1, and MMP-9 were higher in psoriasis than in control subjects. Basal productions of MMP-1, MMP-2, and MMP-9 by monocytes were higher in psoriasis than in controls, while TIMP-1 production was lower. TNF stimulation increased all MMPs in psoriasis and controls; TIMP-1 production was unchanged. IL-17 stimulation increased all MMPs in psoriasis and controls and decreased TIMP-1 production only in psoriasis. MMP-9 production was higher in monocytes stimulated with IL-17 compared to TNF in psoriasis and controls. TIMP-1 production decreased more with IL-17 than with TNF, but only in cells from psoriasis patients. MMP-1/TIMP-1, MMP-2/TIMP-1, and MMP-9/TIMP-1 ratios were higher after IL-17 stimulation (compared to TNF stimulation) in psoriasis; this occurred in monocytes from controls only for the MMP-2/TIMP-1 ratio. In conclusion, IL-17 has a greater capacity than TNF to dysregulate the balance between MMPs and their tissue inhibitor. This hierarchical supremacy supports the blockade of IL-17 as the first line of treatment in plaque psoriasis over TNF inhibitors.