Introduction/Aim:
Rheumatoid arthritis (RA) is an inflammatory and destructive autoimmune polyarthritis which affects approximately 2% of Australians. While clinical trials targeting GM-CSF in RA are showing promise, the potential side effects of anti-GM-CSF therapy highlight the need for identifying downstream mediators of GM-CSF-activated pathway. CCL17, a downstream inflammatory mediator of GM-CSF, has been shown to mediate GM-CSF-driven inflammatory arthritis in animal models. Unlike CCL22, which has a role in resolving inflammation, CCL17 levels are elevated in RA synovial fluid and plasma. Here, a panel of FDA-approved drugs were screened to identify candidate CCL17-inhibiting drugs
Methods:
Human monocytes and mouse macrophages were pre-treated with FDA-approved drugs followed by treatment with either PBS or GM-CSF for 16h. Culture supernatants were subjected to CCL17 and CCL22 ELISA. The effect of drugs on cells viability was confirmed by MTT assay.
Results:
Among 1,508 FDA-approved drugs, 14 drugs inhibited the levels of CCL17 but not CCL22 expression robustly in human monocytes without cytotoxicity. Among 14 drugs, seven drugs inhibited the levels of CCL17 but not CCL22 expression in mouse macrophages.
Conclusions:
Identifying CCL17-inhibiting drugs and repurposing them would be both time-saving and cost-effective. The potency of identified CCL17-inhibiting drugs in blocking arthritis pain and disease development will be assessed in preclinical models.