Differential regulation of chemotaxis: role of Gßγ in chemokine receptor-induced cell migration.

CC and CXC chemokine receptor signalling networks are regulated in different ways. Here we show that intracellular calcium release and cell migration occur independent of Gßγ activation in response to CCL3, whereas CXCL11 induced migration of activated T-lymphocytes depends on Gßγ activation. Treatment of a range of cell types with gallein, a pharmacological inhibitor of Gßγ signalling, did not result in a reduction in CCL3 induced cellular migration, but resulted in enhanced calcium mobilisation following chemokine stimulation. Inhibition of PI3 kinase (PI3K) and AKT, which are activated downstream of Gßγ, equally had no effect on calcium release and a minor effect on cell migration. Similarly, inhibition of ERK1/2 did not prevent CCL3 induced migration. Interestingly, Gßγ as well as PI3K activation is necessary for CXCL11 induced migration of activated T-cells. These data not only confirm a role for Gßγ signalling in CXCL11 induced migration, but also demonstrate that targeting Gßγ as a therapeutic target to prevent migration in inflammatory disease may not be beneficial, at least not for CCL3 induced migration. This highlights the distinct differences in the mechanisms on how CC- and CXC-receptors activate cellular migration.