Prolonged Expression of Interferon‐Inducible Protein‐10 in Ischemic Cortex After Permanent Occlusion of the Middle Cerebral Artery in Rat

Abstract

Focal cerebral ischemia elicits local inflammatory reaction as demonstrated by the accumulation of inflammatory cells and mediators in the ischemic brain. Interferon‐inducible protein‐10 (IP‐10) is a member of the C‐X‐C chemokine family that possesses potent chemoattractant actions for monocytes, T cells, and smooth muscle cells. To investigate a potential role of IP‐10 in focal stroke, we studied the temporal expression of IP‐10 mRNA after occlusion of the middle cerebral artery in rat by means of northern analysis. IP‐10 mRNA expression after focal stroke demonstrated a unique biphasic profile, with a marked increase early at 3 h (4.9‐fold over control; p < 0.01), a peak level at 6 h (14.5‐fold; p < 0.001) after occlusion of the middle cerebral artery, and a second wave induction 10–15 days after ischemic injury (7.2‐ and 9.3‐fold increase for 10 and 15 days, respectively; p < 0.001). In situ hybridization confirmed the induced expression of IP‐10 mRNA and revealed its spatial distribution after focal stroke. Immunohistochemical studies demonstrated the expression of IP‐10 peptide in neurons (3–12 h) and astroglial cells (6 h to 15 days) of the ischemic zone. To explore further the potential role of IP‐10 in focal stroke, we demonstrated a dose‐dependent chemotactic action of IP‐10 on C6 glial cells and enhanced attachment of rat cerebellar granule neurons. Taken together, the data suggest that ischemia induces IP‐10, which may play a pleiotropic role in prolonged leukocyte recruitment, astrocyte migration/activation, and neuron attachment/sprouting after focal stroke.

The opioid antagonist, β-funaltrexamine, inhibits chemokine expression in human astroglial cells

“…Astroglial expression of CXCL10 has also been observed in ischemic stroke. For example, after occlusion of the middle cerebral artery in rat, CXCL10 mRNA expression in cortical tissues peaked 6 h after occlusion, and a second induction of CXCL10 was noted from 10-15 d post-occlusion (Wang et al, 1998). Immunohistochemical analysis of the ischemic cortex indicated CXCL10 protein predominated in the astrocytes of the cortical, striatal and white matter regions surrounding the lesions, as indicated by co-localization of CXCL10 and glial fibrillary acidic protein (Wang et al, 1998).…”

“…Importantly, chemokines have emerged as key molecules involved in neuropathological events and depending on the cellular context can either be neurotoxic or neuroprotective. In particular, CNS levels of the chemokine CXCL10 (formerly referred to as interferon-γ inducible protein or IP-10) are elevated in Alzheimer's disease (Xia et al, 2000), HIV dementia (Cinque et al, 2005;Kolb et al, 1999), ischemic stroke (Wang et al, 1998;Wang et al, 2000) and following spinal cord injury (Gonzalez et al, 2003). We are primarily interested in CXCL10, which is a member of the CXC or α-chemokine family, all of which have four highly conserved cysteine residues with the first two cysteines separated by a single amino acid (Bajetto et al, 2002;Luster et al, 1985).…”

Chronic CXCL10 alters the level of activated ERK1/2 and transcriptional factors CREB and NF-κB in hippocampal neuronal cell culture

“…The CXC chemokine ligand 10 (CXCL10) is thought to play an important role in neuroinflammatory diseases and its action may involve neuronal cells (van Marle et al, 2004). During CNS neuroinflammation expression of CXCL10 is elevated several fold (Franciotta et al, 2001;Kieseier et al, 2002;Kolb et al, 1999;Letendre et al, 1999;Sorensen et al, 1999;Xia et al, 2000) and occurs in a variety of CNS cells including astrocytes, microglia, and neurons (Asensio and Campbell, 1999;Carter et al, 2007;Kutsch et al, 2000;Ransohoff et al, 1993;Rossi and Zlotnik, 2000;Shen et al, 2006;Simpson et al, 2000;Wang et al, 1998).…”

Estrogen and Brain Protection

“…Wang et al, 1994), and interferon inducible protein-10 (IP-10) (X. Wang et al, 1998). The subsequent degeneration of lymphoid organs leads to immunodepression.…”