Synergistic increases in intracellular Ca²⁺, and the release of MCP‐1, RANTES, and IL‐6 by astrocytes treated with opiates and HIV‐1 Tat

Abstract

Recent evidence suggests that injection drug users who abuse heroin are at increased risk for CNS complications from human immunodeficiency virus (HIV) infection. Opiate drugs may intrinsically alter the pathogenesis of HIV by directly modulating immune function and by directly modifying the CNS response to HIV. Despite this, the mechanisms by which opiates increase the neuropathogenesis of HIV are uncertain. Herein we describe the effect of morphine and the HIV-1 protein toxin Tat 1-72 on astroglial function in cultures derived from ICR mice. Astroglia maintain the blood brain barrier and influence inflammatory signaling in the CNS. Astrocytes can express μ opioid receptors, and are likely targets for abused opiates, which preferentially activate μ-opioid receptors. While Tat alone disrupts astrocyte function, when combined with morphine, Tat causes synergistic increases in [Ca 2+ ] i. . Moreover, astrocyte cultures treated with morphine and Tat showed exaggerated increases in chemokine release including monocyte chemoattractant protein-1 (MCP-1) and regulated on activation, normal T cell expressed and secreted (RANTES), as well as interleukin-6 (IL-6). Morphine-Tat interactions were prevented by the μ-opioid receptor antagonist β-funaltrexamine, or by immunoneutralizing Tat 1-72 or substituting a non-toxic, deletion mutant (Tat Δ31-61 ). Our findings suggest that opiates may increase the vulnerability of the CNS to viral entry (via recruitment of monocytes/macrophages) and ensuing HIV encephalitis by synergistically increasing MCP-1 and RANTES release by astrocytes. The results further suggest ‡ Abbreviations: alpha chemokine receptor (CXCR); beta chemokine ligand (CCL); beta chemokine receptor (CCR); β-funaltrexamine (β-FNA); calcium-induced calcium release (CICR); excitatory amino acid transporter-2 (EAAT2); granulocyte macrophage colony stimulating factor (GM-CSF); granulocyte-colony stimulating factor (G-CSF); human immunodeficiency virus (HIV); human immunodeficiency virus encephalitis (HIVE); inositol trisphosphate (IP 3 ); interferon (IFN); interleukin (IL); intracellular Ca 2+ ([Ca 2+ ] i ); monocyte chemoattractant protein (MCP); nor-binaltorphimine (nor-BNI); phosphatidylinositol 3-kinase (PI3-kinase); phospholipase C-γ (PLCγ); regulated on activation, normal T cell expressed and secreted (RANTES); soluble TNF receptor subunit (sTNFR1); stem cell factor (SCF); thrombopoietin (TPO); transactivator of transcription (Tat); tumor necrosis factor-α (TNF-α); vascular endothelial growth factor (VEGF).

Differential involvement of p38 and JNK MAP kinases in HIV-1 Tat and gp120-induced apoptosis and neurite degeneration in striatal neurons

“…Another explanation is that MLK3 has also been recently reported to modulate p38 MAPK activity (in addition to JNK) , suggesting that p38 MAPK may have also been involved in gp120-induced hippocampal neuron losses. Lastly, although our striatal cultures are highly enriched in neurons (Singh et al, 2004), with negligible microglia (~0.14%) or astroglia (~1%), we cannot exclude the possibility that contaminating glia might mediate some aspects of Tat or gp120 neurotoxicity (Vesce et al, 1997;El-Hage et al, 2005). Studies in progress are specifically addressing this issue.…”

Astrocytes are a neural target of morphine action via glucocorticoid receptor‐dependent signaling

“…It has been shown that acute morphine stimulation can induce calcium signaling El-Hage et al, 2005) and ERK phosphorylation (Belcheva et al, 2003), while prolonged exposure affected proliferation (Stiene-Martin et al, 2001) and proteomic profile (Suder et al, 2009) in primary astrocytes. The absence of direct transcriptional effects of morphine in astrocytes in the current study may be explained by the low level of l opioid receptors in our cultures, which is consistent with previous reports (Ruzicka et al, 1995;Stiene-Martin et al, 1998).…”

Direct Evidence of Astrocytic Modulation in the Development of Rewarding Effects Induced by Drugs of Abuse

“…In the present study, some chemokiens, such as MCP-5 and sTNFR1, were identified in ACM and METH-ACM. MCP-5 is a mouse homologue to MPC-1 (El-Hage et al, 2005). In addition, treatment with MRP induces the secretion of MCP-1 from astrocytes (El-Hage et al, 2005).…”

“…MCP-5 is a mouse homologue to MPC-1 (El-Hage et al, 2005). In addition, treatment with MRP induces the secretion of MCP-1 from astrocytes (El-Hage et al, 2005). On the other hand, the biological functions of the sTNFR1 are not completely understood.…”