Technical Abstract: Protease activated receptors (PARs) are expressed on structural cells and immune cells. Control of the initiation, duration, and magnitude of the PAR effects are linked to the level of receptor expression, the availability of proteases, and the intracellular signal transduction machinery. We investigated nematode infection-induced changes in PAR2 expression and their impact on smooth muscle and epithelial responses to PAR2 agonists. Smooth muscle and epithelial cell function were assessed in wild type BALB/c, and IL-4, IL-13, or STAT6 gene-deficient mice following treatment with vehicle, the parasitic nematodes Nippostrongylus brasiliensis or Heligmosomoides polygyrus, or IL-13. The role of enteric nerves was determined using tetrodotoxin to block nerve conduction. Expression of PAR2 was assessed by real-time PCR and immune histochemistry. Nematode infection induced a STAT6- and IL-13-dependent up-regulation of PAR2 mRNA expression. The infection-induced hyper-contractility to PAR2 agonists required STAT6/IL-13 and was neuron-mediated. In contrast, the infection-induced decrease in epithelial secretion to PAR2 agonists was partly dependent on STAT6 and was independent of enteric nerves. Hypo-secretion was correlated with decreased PAR2 on epithelial cells, but enhanced staining of cells in the lamina propria. This study demonstrated novel immune regulation of PAR2 expression that directly impacted both smooth muscle and epithelial cell responses to PAR2 agonists with differences related to the contribution of enteric nerves. These data provided a mechanism by which activation of PAR2 in immune-based pathologies can induce both transient and long-lasting changes in gut function.