Regulation of the Release of Interleukin‐6 from Human Astrocytoma Cells

Abstract

Recent evidence suggests that the level of interleukin‐6 (IL‐6) is elevated in Alzheimer's disease (AD) brains. IL‐6 is produced by reactive glial cells and could potentially affect neuronal survival. Understanding the biochemical mechanism that regulates the production and release of IL‐6 by astrocytic cells may help to identify potential targets for therapeutic intervention in AD. In the present study, glial fibrillary acidic protein‐positive human U373MG astrocytoma cells were used as a model of reactive astrocytes. Production of IL‐6 in response to drug treatment was monitored with an ELISA assay. Histamine (1–100 µM), substance P (SP; 1–100 nM), and human interleukin‐1β (IL‐1β; 1–30 pM) stimulated the release of IL‐6 in a time‐ and concentration‐dependent manner, with EC50 values of 4.5 µM, 8 nM, and 4.5 pM, respectively. The respective effects of histamine, SP, and IL‐1β were effectively blocked by the histamine H1, SP, and IL‐1 receptor antagonists, supporting a receptor‐mediated event for these agents. Both histamine and SP enhanced the formation of inositol phosphates and increase intracellular calcium levels, suggesting that the phosphatidyl‐inositol bisphosphate/protein kinase C pathway may be involved in the IL‐6 release process. Indeed, phorbol 12‐myristate 13‐acetate, a protein kinase C activator, also evoked IL‐6 release from the U373MG cells. On the other hand, IL‐1β, which produces a much more robust release of IL‐6 than histamine or SP, has no effect on inositol phosphate formation or intracellular calcium levels. The biochemical mechanism of the release of IL‐6 in response to IL‐1β remains to be elucidated.

Spinal Glia and Proinflammatory Cytokines Mediate Mirror-Image Neuropathic Pain in Rats

“…It also synergizes with lipopolysaccharide, enhancing IL1 release (Martin et al, 1993). Furthermore, substance P releases IL6 and prostaglandins from astrocytes (Marriott et al, 1991;Cadman et al, 1994;Gitter et al, 1994). Indeed, astrocytes in spinal cord, but not astrocytes isolated from various brain regions, release prostaglandins in response to substance P (Marriott et al, 1991), suggesting that spinal glia are uniquely responsive to neurotransmitters in dorsal horn.…”

Iron: The Redox-active Center of Oxidative Stress in Alzheimer Disease

“…Activated microglia also release iron from ferritin in a superoxide dependent fashion and result in lipid oxidation in vivo [55]. In fact, elevated levels of IL-1 and IL-6 in AD brain have been reported [56]. Whether such microglial activation, like amyloid-b activation [51], is mediated by iron is unclear.…”

Enforced Expression of Superoxide Dismutase 2/Manganese Superoxide Dismutase Disrupts Autocrine Interleukin-6 Stimulation in Human Multiple Myeloma Cells and Enhances Dexamethasone-Induced Apoptosis

“…One of the most commonly encountered ligands that function via an autocrine loop in tumor cells is the pleiotropic cytokine, interleukin-6 (IL-6). IL-6 is known to play a role in the growth and survival of astrocytomas (8), B-lymphomas (9), and gliomas (10) as well as bladder (11), cervical (12), renal (13), and prostatic (14) carcinomas. In multiple myeloma, IL-6 serves as a potent growth factor and also functions to block dexamethasone-induced apoptosis (15).…”