Synergistic induction of CXCL10 by interferon-gamma and lymphotoxin-alpha in astrocytes: Possible role in cerebral malaria

Cerebral malaria (CM) has a high mortality rate and incidence of neurological sequelae in survivors. Hypoxia and cytokine expression in the brain are two mechanisms thought to contribute to the pathogenesis of CM. The cytokines interferon (IFN)-gamma and lymphotoxin (LT)-alpha and the chemokine CXCL10 are essential for the development of CM in a mouse model. Furthermore, serum IFN-gamma protein levels are higher in human CM than in controls, and CXCL10 is elevated in both serum and cerebrospinal fluid in Ghanaian paediatric CM cases. Astrocytes actively participate in CNS pathologies, becoming activated in response to various stimuli including cytokines. Astrocyte activation also occurs in murine and human CM. We here determined the responsiveness of mouse and human astrocytes to MN-7 and LT-alpha, with the aim of further elucidating the role of astrocytes in CM pathogenesis. Initially we confirmed that Ifn-gamma and Cxcl10 are expressed in the brain in murine CM, and that the increased Cxcl10 expression is IFN-gamma-dependant. IFN-gamma induced CXCL10 production in human and murine astrocytes in vitro. The degree of induction was increased synergistically in the presence of LT-alpha IFN-gamma induced the expression of receptors for LT-alpha, while LT-alpha increased the expression of the receptor for IFN-gamma, in the astrocytes. This cross-induction may explain the synergistic effect of the two cytokines on CXCL10 production. Expression of these receptors also was upregulated in the brain in murine CM. The results suggest that astrocytes contribute to CM pathogenesis by producing CXCL10 in response to IFN-gamma and LT-alpha. (C) 2015 Elsevier Ltd. All rights reserved.