TIMP-1 couples RhoK activation to IL-1β-induced astrocyte responses

Interleukin-1 beta (IL-1 beta) is a pleotropic cytokine known to influence the central nervous system (CNS) responses to injury or infection. IL-1 beta also directly induces astrocytic expression of tissue inhibitor of metalloproteinases (TIMP)-1, a potent trophic factor and regulator of matrix metalloproteinase activity. In this study, we examined the functional relationship between IL-1 beta and TIMP-1 and determined that the behavior of astrocytes in response to IL-1 beta is determined by TIMP-1 expression. Using primary astrocytes from C57Bl/6 mice, we found astrocytes from wildtype (Wt) mice exhibited a robust wound healing response to a scratch wound that was arrested in response to IL-1 beta. In contrast, TIMP-1 knockout (TIMP-1KO) astrocytes, exhibited minimal response to the scratch wound but an accelerated response following IL-1 beta-treatment. We also determined that the scratch wound effect in Wt cultures was attenuated by inhibition of Rho kinase but amplified in the TIMP-1KO cultures. We propose that the specific induction of TIMP-1 from astrocytes in response to IL-1 beta reflects a previously unrecognized physiological relationship where the directionality of astrocytic behavior is determined by the actions of TIMP-1. These findings may provide additional insight into glial responses in the context of neuropathology where expression of TIMP-1 may vary and astrocytic responses may be impacted by the inflammatory milieu of the CNS. (C) 2015 Elsevier Ireland Ltd. All rights reserved.