Unmasking of LPA.

Action mechanism of lipopolysaccharide (LPS), interleukin-1β (IL-1β), and lysophosphatidic acid (LPA) to regulate motility, an important process of astrogliosis, was investigated in rat astrocytes. While LPA exerted no significant effect on the cell migration, the prior treatment of the cells with LPS or IL-1β resulted in the appearance of migration activity in response to LPA. The LPS induction of the migration response to LPA was associated with the production of IL-1β precursor protein and inhibited by the IL-1 receptor antagonist. The IL-1β treatment also allowed LPA to activate Rac1. The LPA-induced Rac1 activation and migration were inhibited by pertussis toxin, a small interfering RNA specific to LPA₁ receptors, and LPA₁ receptor antagonists, including Ki16425. However, the IL-1β treatment had no appreciable effect on LPA₁ receptor mRNA expression and LPA-induced activation of ERK, Akt, and proliferation. The induction of the migration response to LPA by IL-1β was inhibited by a constitutively active RhoA. Moreover, LPA significantly activated RhoA through the LPA₁ receptor in the control cells but not in the IL-1β-treated cells. These results suggest that IL-1β inhibits the LPA₁ receptor-mediated Rho signaling through the IL-1 receptor, thereby disclosing the LPA₁ receptor-mediated G_i protein/Rac/migration pathway. [ABSTRACT FROM AUTHOR]