Roflumilast Reduced the IL-18-Induced Inflammatory Response in Fibroblast-Like Synoviocytes (FLS)

Abstract

Pro-inflammatory cytokines, such as the IL-18-induced inflammatory response and associated damage in fibroblast-like synoviocytes (FLS), play an important role in the pathogenesis of rheumatoid arthritis (RA). Roflumilast, an inhibitor of phosphodiesterase-4 (PDE-4), has been licensed for the treatment of chronic obstructive pulmonary disease (COPD). However, it is unknown whether roflumilast possesses a protective effect against the IL-18-induced inflammatory response in FLS. We found that roflumilast attenuated IL-18-induced oxidative stress by reducing the production of reactive oxygen species and malondialdehyde (MDA) in MH7A fibroblast-like synoviocytes (FLS). Additionally, roflumilast prevented IL-18-induced expressions and secretions of pro-inflammatory cytokines such as IL-6, IL-8, and TNF-α. Importantly, we found that roflumilast inhibited IL-18-induced expressions of chemokines such as CCL5, CXCL9, and CXCL10. Further, roflumilast inhibited the expression of extracellular matrix degradative enzymes, such as matrix metalloproteinase-3 (MMP-3) and MMP-13. Mechanistically, we found that roflumilast suppressed the activation of the transcriptional factor AP-1 and NF-κB. Our results suggest that roflumilast might be a potential therapeutic agent for the treatment of RA.

Severity of neonatal influenza infection is driven by type I interferon and oxidative stress

“…To directly assess the relative contribution of superoxide production to the oxidative stress imbalance, we employed dihydroethidium (DHE) staining coupled to multicolor flow cytometry. DHE can directly measure the amount of ROS in live cells with specificity for superoxide and hydrogen peroxide ( 51 ). Again, neonatal and adult mice were infected with IV, and lungs were harvested 2-days post infection.…”

Longstanding hypersensitivity pneumonitis and its response to roflumilast: A review of its likely immunological effects

“…Roflumilast has anti-inflammatory effects in COPD and asthma by increasing levels of intracellular cyclic AMP and changing mediator release ( Table 2 ) [ 26 , [31] , [32] , [33] , [34] ]. It significantly reduces cellular influx into the lung, microvascular leak and reduces a range of pro-inflammatory mediators upon antigen challenge in animal models.…”

“…Interleukin-18(IL-18) comes from a wide range of immune cells with its main function to stimulate lymphocytes to produce IFNγ and regulate cell activity by increasing further IL8, TNFα and IL-6 [ 6 , 20 , 31 , 37 ]. Roflumilast reduces IL18 production in a dose dependant way which also produces an inhibitory effect on IL-17 production and these various actions may be the basis of roflumilast action in this patient [ 31 ].…”

“… ↓ 12 IL-10 Produced by Tregs and reduces antigen presentation with tolerogenic effects on dendritic cells ↑↑ 30 Fibroblast growth factor Activates fibrotic processes + wound repair ↓ 38 IL-18 Stimulates lymphocytes to produce IFN-γ secretion that drives TNFα, IL-17 + IL-6 production. ↓↓ 31 Il-1β From monocytes + dendritic cell enhanced by IL-17 and drives further IL-17 + TNFα production that reduces Tregs function ↓↓ 25 Interleukin-6 ↑ IFN-γ production by monocytes + B cells ↓ 38 …”

Clinical Implication of Phosphodiesterase-4-Inhibition

“…In vitro, roflumilast decreased IL-18 induced oxidative stress (ROS and MDA) in FS. Roflumilast reduced the secretion of MMP3, MMP13, CCL5, CXCL9 and CXCL10 in FS and had an inhibitory effect on NF-κB and AP-1 [122].…”