Cytokines in inflammatory brain lesions: helpful and harmful

Merrill, Jean E.; Benveniste, Etty N.

doi:10.1016/0166-2236(96)10047-3

Cited by 667 publications

(385 citation statements)

References 61 publications

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“…First pro-inflammatory cytokines appear to block the analgesic effects of opioids [41,42], which may explain the decreased efficacy of morphine in Experiment 1. Second, pro-inflammatory cytokines have been linked to cytotoxic effects in the nervous system [43,44,45]. Yang et al [36] suggest that there is a critical balance between beneficial and toxic effects that depends on cytokine concentrations.…”

Section: Discussionmentioning

confidence: 99%

The impact of morphine after a spinal cord injury

Hook

Liu

Washburn

et al. 2007

Behavioural Brain Research

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Nociceptive stimulation, at an intensity that elicits pain-related behavior, attenuates recovery of locomotor and bladder functions, and increases tissue loss after a contusion injury. These data imply that nociceptive input (e.g., from tissue damage) can enhance the loss of function after injury, and that potential clinical treatments, such pretreatment with an analgesic, may protect the damaged system from further secondary injury. The current study examined this hypothesis and showed that a potential treatment (morphine) did not have a protective effect. In fact, morphine appeared to exacerbate the effects of nociceptive stimulation. Experiment 1 showed that after spinal cord injury 20 mg/kg of systemic morphine was necessary to induce strong antinociception and block behavioral reactivity to shock treatment, a dose that was much higher than that needed for sham controls. In Experiment 2, contused rats were given one of three doses of morphine (Vehicle, 10, 20 mg/kg) prior to exposure to uncontrollable electrical stimulation or restraint alone. Despite decreasing nociceptive reactivity, morphine did not attenuate the long-term consequences of shock. Rats treated with morphine and shock had higher mortality rates, and displayed allodynic responses to innocuous sensory stimuli three weeks later. Independent of shock, morphine per se undermined recovery of sensory function. Rats treated with morphine alone also had significantly larger lesions than those treated with saline. These results suggest that nociceptive stimulation affects recovery despite a blockade of pain-elicited behavior. The results are clinically important because they suggest that opiate treatment may adversely affect the recovery of function after injury.

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Section: Discussionmentioning

confidence: 99%

The impact of morphine after a spinal cord injury

Hook

Liu

Washburn

et al. 2007

Behavioural Brain Research

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“…Possible candidates here might include the cytokines IFN-␥ and TNF whose expression was induced in the brain of the GF-IL-12 mice. These cytokines have been implicated as mediators of cellular injury during inflammatory responses in the CNS (60,61).…”

Section: Discussionmentioning

confidence: 99%

Astrocyte-Targeted Expression of IL-12 Induces Active Cellular Immune Responses in the Central Nervous System and Modulates Experimental Allergic Encephalomyelitis

Pagenstecher¹,

Laßmann²,

Carson

et al. 2000

The Journal of Immunology

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The role of IL-12 in the evolution of immunoinflammatory responses at a localized tissue level was investigated. Transgenic mice were developed with expression of either both the IL-12 subunits (p35 and p40) or only the IL-12 p40 subunit genes targeted to astrocytes in the mouse CNS. Glial fibrillary acidic protein (GF)-IL-12 mice, bigenic for the p35 and p40 genes, developed neurologic disease which correlated with the levels and sites of transgene-encoded IL-12 expression. In these mice, the brain contained numerous perivascular and parenchymal inflammatory lesions consisting of predominantly CD4+ and CD8+ T cells as well as NK cells. The majority of the infiltrating T cells had an activated phenotype (CD44high, CD45Rblow, CD62Llow, CD69high, VLA-4 high, and CD25+). Functional activation of the cellular immune response was also evident with marked cerebral expression of the IFN-γ, TNF, and IL-1αβ genes. Concomitant with leukocyte infiltration, the CNS expression of immune accessory molecules was induced or up-regulated, including ICAM-1, VCAM-1, and MHC class II and B7-2. Glial fibrillary acidic protein-p40 mice with expression of IL-12 p40 alone remained asymptomatic, with no inflammation evident at any age studied. The effect of local CNS production of IL-12 in the development of experimental autoimmune encephalomyelitis was studied. After immunization with myelin oligodendrocyte glycoprotein-peptides, GF-IL-12 mice had an earlier onset and higher incidence but not more severe disease. We conclude that localized expression of IL-12 by astrocytes can 1) promote the spontaneous development of activated type 1 T cell and NK cellular immunity and cytokine responses in the CNS, and 2) promote more effective Ag-specific T cell dynamics but not activity in experimental autoimmune encephalomyelitis.

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“…MS lesions contain a large number of proinflammatory products from activated microglia and macrophages that are highly toxic to myelin sheets, oligodendrocytes, and neurons (Selmaj and Raine, 1988;Selmaj et al, 1991;Probert et al, 1995;Merrill and Benveniste, 1996;Raivich and Banati, 2004;Sospedra and Martin, 2005). We have shown in our cell culture systems that phagocytosis of myelin affects microglial inflammatory activity: after an initial (first hours) increase in transcription and secretion of inflammatory microglial products, consistent with previous reports on proinflammatory effects of myelin phagocytosis (Williams et al, 1994;Mosley and Cuzner, 1996;van der Laan et al, 1996), phagocytosis of myelin, however, strongly suppressed microglial inflammatory activation at a late phase as demonstrated by the pronounced downregulated production of inflammatory cytokines and chemokines.…”

Section: Discussionmentioning

confidence: 99%

Suppression of Microglial Inflammatory Activity by Myelin Phagocytosis: Role of p47-PHOX-Mediated Generation of Reactive Oxygen Species

Liu¹,

Hao²,

Letièmbre³

et al. 2006

J. Neurosci.

111

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Multiple sclerosis (MS) is pathologically characterized by inflammatory demyelination and neuronal injury. Although phagocytosis of myelin debris by microglia and macrophages in acute MS lesions is well documented, its pathophysiological significance is unclear. Using real-time quantitative PCR, flow cytometry, ELISA, and reactive oxygen species (ROS) measurement assays, we demonstrated that phagocytosis of myelin modulates activation of microglial cells prestimulated by interferon-␥ (IFN-␥) or a combination of IFN-␥ and lipopolysaccharide with a biphasic temporal pattern, i.e., enhanced production of proinflammatory mediators during the first phase (Յ6 h), followed by suppression during the second (6 -24 h) phase. In this second phase, myelin phagocytosis leads to an enhanced release of prostaglandin E2 and ROS in microglia, whereas the production of anti-inflammatory cytokines (particularly interleukin-10) remains unchanged. Suppression of inflammatory microglial activation by myelin phagocytosis was reversed by treatment with superoxide dismutase and catalase, by inhibition of the NADPH-oxidase complex, or by specific knockdown of the NADPH-oxidase-required adaptor p47-phagocyte oxidase (PHOX). Furthermore, we observed that myelin phagocytosis destabilized tumor necrosis factor-␣ and interferon-induced protein-10 mRNA through an adenine-uridine-rich elements-involved mechanism, which was reversed by blocking the function of NADPH-oxidase complex. We conclude that phagocytosis of myelin suppresses microglial inflammatory activities via enhancement of p47-PHOX-mediated ROS generation. These results suggest that intervention in ROS generation could represent a novel therapeutic strategy to reduce neuroinflammation in MS.

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Cytokines in inflammatory brain lesions: helpful and harmful

Cited by 667 publications

References 61 publications

The impact of morphine after a spinal cord injury

The impact of morphine after a spinal cord injury

Astrocyte-Targeted Expression of IL-12 Induces Active Cellular Immune Responses in the Central Nervous System and Modulates Experimental Allergic Encephalomyelitis

Suppression of Microglial Inflammatory Activity by Myelin Phagocytosis: Role of p47-PHOX-Mediated Generation of Reactive Oxygen Species

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