TNF and major depressive disorder: However, long-term systemic inflammation has been suggested as a plausible explanation, supported by the association of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and other chemokines with both RA and depression.29 These cytokines cross the blood-brain barrier, interacting with the brain and triggering microglial activation, releasing proinflammatory factors.30,31,32 Neural pathways also transmit peripheral inflammation signals to the central nervous system (CNS), inducing CNS inflammation.