Blood vitronectin is a major activator of LIF and IL-6 in the brain through integrin-FAK and uPAR signaling

Abstract

We defined how blood-derived vitronectin (VTN) rapidly and potently activates leukemia inhibitory factor (LIF) and pro-inflammatory interleukin 6 (IL-6) in vitro and after vascular injury in the brain. VTN (not fibrinogen, fibronectin, laminin-111, collagen-I) robustly increased LIF and IL-6 within 4 hr in C6-astroglioma cells, while VTN-/- mouse plasma was less effective than wildtype. LIF and IL-6 were induced by intracerebral injection of rhVTN in mice, but less by intracerebral hemorrhage in VTN-/- than wildtype littermates. In vitro, VTN effects were inhibited by RGD,αvβ3 and avb5 integrin blocking peptides, and antibodies. VTN activated focal adhesion kinase (FAK), whereas pharmacological or siRNA inhibition of FAK, but not PYK2, reduced LIF and IL-6 in C6 and endothelial cells, and after traumatic cell injury. Dominant negative FAK (Y397F) reduced injury-induced LIF and IL-6. Pharmacological inhibition or knockdown of uPAR, which binds VTN, also reduced cytokine expression, possibly through a common target of uPAR and integrins. We propose that VTN leakage into tissues promotes inflammation. Integrin-FAK signaling is a novel IL-6 and LIF regulation mechanism relevant to the inflammation and stem cell fields.