Abstract
Despite strong evidence supporting the cellular interplay between haemostasis and
innate immunity, humoral connections between blood coagulation and the behavior of
inflammatory macrophages are not well understood. In this study, we investigated changes
in gene expression of selected cytokines and chemokines and their secretion profiles
following thrombin stimulation of murine macrophages. Thrombin promoted differentiation
of macrophages into an M1-like phenotype that was associated with the expression of
classical pro-inflammatory markers. The cellular actions of thrombin on macrophages
were mediated in part by protease-activated receptor-1 (PAR-1) and were dependent
on phosphoinositide 3-kinase/AKT and nuclear factor-κB. Moreover, heat-denatured thrombin
stimulated the secretion of some pro-inflammatory mediators to the same magnitude
indicating that different receptors transmit cellular signals of enzymatically active
thrombin and nonactive thrombin, the latter remaining so far undefined. Finally, pretreatment
of macrophages with thrombin resulted in tolerance against secondary stimulation by
lipopolysaccharide with regard to expression of tumor necrosis factor-α. These results
provide new insights into the molecular link between the key enzyme of haemostasis
and innate immunity responses.
Keywords
thrombin receptors - tumor necrosis factor-α - protease-activated receptors - cytokine
profile - innate immunity
