Syndecan-4 is a transmembrane heparan sulfate proteoglycan belonging to the syndecan family. Syndecan-4-deficient [(Synd4(−/−)] mice were produced to clarify the in vivo role of syndecan-4. Synd4(−/−) mice were more susceptible to κ-carrageenan-induced nephropathy, and the placental labyrinth from the deficient embryos exhibited more thrombi than wild-type ones. Importantly, Synd4(−/−) mice were more susceptible to endotoxin shock. Further analysis revealed that the mechanism to suppress excessive production of interleukin-1β (1L-1β) by transforming growth factor-β (TGF-β) was impaired in the deficient mice. TGF-β, one of the cytokines involved in the suppression mechanism, bound to heparan sulfate chain of syndecan-4, which was induced in macrophages and the microvasculature after administration of lipopolysaccharide. Therefore, augmentation of TGF-β function by induced syndecan-4 was suggested as a mechanism of the suppressive action of syndecan-4 against endotoxin shock. Published in 2003.