For instance, TNF-α, a pleiotropic cytokine synthesized by many cell types, is essential for the immune cascade response, primarily mediating stress-activated protein kinase/milk mitogen-activated protein kinase (SAPK/MAPK) pathway signaling and activating JAK/STAT signaling, which serves as the major trigger of inflammation and joint damage in RA (24). Here, TNF is linked to rheumatoid arthritis.