We reported that sphingosine 1-phosphate type2 receptor (S1P₂)/Rho kinase pathway is necessary for full activation of STAT6 by IL-4/IL-13 in phorbol ester-treated THP-1 macrophages (MΦs) at the 94th Annual Meeting of the Japanese Pharmacological Society. This time, we report the further results.  The S1P₂^knockout THP-1 MΦs showed lower activities of STAT6 phosphorylation in response to IL-4 or IL-13 stimulation than the wild-type THP-1 MΦs. This decrease in IL-4-induced STAT6 phosphorylation in the S1P₂^knockout THP-1 MΦs was prevented by ectopic expression of mouse S1pr2. S1P₂ regulates the Rho/Rho kinase pathway. Pretreatment of THP-1 MΦs with Rho inhibitor Rhosin inhibited the IL-4-induced increase in STAT6 phosphorylation. STAT activation is tightly controlled by multiple negative regulators of phosphorylation such as protein tyrosine phosphatases (PTPs) and suppressor of cytokine signaling (SOCS). The expressions of SOCS3 in the S1P₂^knockout THP-1 MΦs were higher than those in wild-type THP-1 MΦs and the PTP inhibitor vanadate enhanced IL-4-induced STAT6 phosphorylation in the S1P₂^knockout THP-1 MΦs, suggesting that SOCS3 and PTPs are involved in the positive regulation of IL-4-induced STAT6 phosphorylation by S1P₂. We examined the crosstalk between IL-4/IL-13 and S1P/S1P₂ signaling in PMA-treated THP-1 MΦs. Although IL-4/IL-13 stimulation induced the mRNA expression of S1P₃, those of S1P₁, S1P₂ or RhoA were not induced by IL-4/IL-13. Since S1P₃ has been reported to activate Rho, it is possible that the Rho-Rho kinase pathway is enhanced by IL-4/IL-13 stimulation by this mechanism. These results suggest that pharmacological inhibition of S1P₂/Rho/Rho kinase pathway would attenuate Th2-type immune responses induced by IL-4/IL-13, thereby suppressing allergic diseases.