Protease-activated receptor-1 regulates cytokine production and induces the suppressor of cytokine signaling-3 in microglia.

Protease-activated receptors (PARs) are cleaved and activated by thrombin and other extracellular proteases which are released during tissue trauma and inflammation. PAR-1 is the prototypic member of the PAR family and has been shown to be upregulated in several brain pathologies being expressed by neurons and glial cells. The present experiments show that the administration of the PAR-1 activating peptides (TRAP6 and TFLLR) inhibits the production of the pro-inflammatory cytokines TNF-alpha and IL-6 in microglial cells treated with lipopolysaccharide (LPS) while promoting the release of the anti-inflammatory cytokine IL-10. Conversely, the addition of the specific PAR-2 agonist SLIGRL had no effect on the amount of cytokines released following LPS treatment. Consistent with these data PAR-1, but not PAR-2, stimulation upregulates the expression of the suppressor of cytokine signaling-3 (SOCS-3). The present data support the hypothesis that in microglia PAR-1 may be involved in the regulation of inflammatory reactions modulating the balance between pro- and anti-inflammatory cytokines possibly through SOCS induction.