Prolactin Inhibits or Stimulates the Inflammatory Response of Joint Tissues in a Cytokine-dependent Manner

The close association between rheumatoid arthritis (RA), sex, reproductive state, and stress has long linked prolactin (PRL) to disease progression. PRL has both proinflammatory and anti-inflammatory outcomes in RA, but responsible mechanisms are not understood. Here, we show that PRL modifies in an opposite manner the proinflammatory actions of IL-1 beta and TNF-alpha in mouse synovial fibroblasts in culture. Both IL-1 beta and TNF-alpha upregulated the metabolic activity and the expression of proinflammatory factors (Il1b, Inos, and Il6) via the activation of the nuclear factor-kappa B (NF-kappa B) signaling pathway. However, IL-1 beta increased and TNF-alpha decreased the levels of the long PRL receptor isoform in association with dual actions of PRL on synovial fibroblast inflammatory response. PRL reduced the proinflammatory effect and activation of NF-kappa B by IL-1 beta but increased TNF-alpha-induced inflammation and NF-kappa B signaling. The double-faceted role of PRL against the 2 cytokines manifested also in vivo. IL-1 beta or TNF-alpha with or without PRL were injected into the knee joints of healthy mice, and joint inflammation was monitored after 24 hours. IL-1 beta and TNF-alpha increased the joint expression of proinflammatory factors and the infiltration of immune cells. PRL prevented the actions of IL-1 beta but was either inactive or further increased the proinflammatory effect of TNF-alpha. We conclude that PRL exerts opposite actions on joint inflammation in males and females that depend on specific proinflammatory cytokines, the level of the PRL receptor, and the activation of NF-kappa B signaling. Dual actions of PRL may help balance joint inflammation in RA and provide insights for development of new treatments.