Product ion of the cytokines interleukin 1 and 6 by murine brain microvessel endothelium and smooth muscle pericytes

Fábry, Zsuzsanna; Fitzsimmons, Karen M.; Herlein, Judith A.; Moninger, Thomas O.; Dobbs, Matthew B.; Hart, Michael N.

doi:10.1016/0165-5728(93)90281-3

Cited by 189 publications

(92 citation statements)

References 34 publications

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“…2B). Thus, we reason that the Per2-deficient vascular endothelium, rather than monocytes/macrophages, may be the major cell source of IL-1␤ impairment in response to systemic endotoxin (5,7,12).…”

Section: Vol 74 2006mentioning

confidence: 99%

The Circadian ClockPeriod 2Gene Regulates Gamma Interferon Production of NK Cells in Host Response to Lipopolysaccharide-Induced Endotoxic Shock

Liu¹,

Mankani

Shi³

et al. 2006

Infect Immun

202

102

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The Period 2 (Per2) gene is a key molecular component in controlling mammalian circadian rhythms at the levels of gene expression, physiology, and pathogenesis. Although many immune parameters, such as the number of different subtypes of circulating immune cells and the level of cytokine production in response to infection with bacteria and viruses, have been well documented to display a circadian pattern in mammals, the basic features of molecular clock components in the immune system and the role of clock genes in regulating host immune defenses remain uncharacterized. Previously, we have reported that circadian clock genes oscillate in human mononuclear cells. Here we report that Per2-deficient mice were more resistant to lipopolysaccharide (LPS)-induced endotoxic shock than control wild-type mice. We further demonstrate that the levels of the proinflammatory cytokines gamma interferon (IFN-␥) and interleukin-1␤ (IL-1␤) in the serum were dramatically decreased in Per2 ؊/؊ mice following LPS challenge, while production of tumor necrosis factor alpha, IL-6, and IL-10 was approximately normal, compared to that in control wild-type mice. Flow cytometric analyses confirmed that the cellularity of most of the immune cell subsets in the spleens of LPS-challenged mice was normal and that the impaired IFN-␥ production in Per2 ؊/؊ mice was attributable to defective NK and NKT cell function. Our data suggest that Per2 is an important regulator of NK cell function, therefore providing the first direct link between the circadian clock system and innate immune responses.Circadian rhythms are daily oscillations of multiple biological processes driven by endogenous clocks. The master circadian clock in mammals resides in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. The endogenous clock is further distinguished by its ability to be entrained to a new day/night regimen by environmental cues such as light and temperature cycles (13,27,29). It was originally thought that the mammalian circadian clock system was hierarchically organized; however, while the SCN is a master circadian clock tissue, generating self-sustained circadian oscillators which determine the pace and amplitude of the expression of the circadian clock genes in peripheral tissues through neuronal and hormonal signals, these peripheral clocks in turn control the output of circadian physiology and behavior. However, the details of how the SCNЈs signaling pathway controls the peripheral clock still remain to be elucidated.Circadian rhythms are known to influence the immune response of mammals through their effects on the circulation of the blood as related to diurnal sleeping/waking and activity cycles. Born and coworkers (6) demonstrated that in humans, blood cell compartmentalization, such as with peripheral cell counts of neutrophils, T-lymphocyte subsets, B lymphocytes, monocytes, and natural killer (NK) cells, displays a circadian fluctuation across the day. The peak of each subtype of cells in peripheral blood varies with time. The numbers...

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Section: Vol 74 2006mentioning

confidence: 99%

The Circadian ClockPeriod 2Gene Regulates Gamma Interferon Production of NK Cells in Host Response to Lipopolysaccharide-Induced Endotoxic Shock

Liu¹,

Mankani

Shi³

et al. 2006

Infect Immun

202

102

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“…The positive correlation between the bacterial burdens and these cytokine/chemokine levels in cerebellum homogenates of all mice suggests that the cytokine/chemokine levels depend mainly on the bacterial load and that high cytokine/chemokine concentrations do not reflect resistance to infection. Microglia, perivascular macrophages, astrocytes, and brain endothelial cells produce IL-1␤, IL-6, KC, and MIP-2 in response to experimental stimulation by bacterial agents (9,26,(32)(33)(34). Exposure to viable E. coli induced the release of high levels of tumor necrosis factor alpha (TNF-␣) and KC by primary mouse microglia in a time-of-exposure-dependent manner (S. Ribes, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Resistance of the Brain to Escherichia coli K1 Infection Depends on MyD88 Signaling and the Contribution of Neutrophils and Monocytes

et al. 2013

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“…The pericytes are smooth muscle cells that are in close proximity to the BMVEC (see Figure 1). Although the function of the pericytes in the BBB are still being debated, these cells produce and secrete several immunomodulating agents that can in¯uence immune responses in the CNS (Fabry et al, 1993). The pericytes may also provide a means for contraction of the brain capillaries.…”

Section: Components Of the Bbbmentioning

confidence: 99%

Immunobiology of the blood-brain barrier

Miller¹

1999

J Neurovirol

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The brain microvessel endothelial cells (BMVEC) that form the blood-brain barrier are uniquely positioned to in¯uence immune responses within the central nervous system. As the biological interface separating the blood from the brain extracellular¯uid, BMVEC regulate the entry of leukocytes into the brain. In addition, through the release of various soluble factors that affect immune responses, BMVEC may modulate immune responses in the brain. This review addresses the interplay between the immune system and the blood-brain barrier as it relates to the regulation of CNS defense and immunity.

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Product ion of the cytokines interleukin 1 and 6 by murine brain microvessel endothelium and smooth muscle pericytes

Cited by 189 publications

References 34 publications

The Circadian ClockPeriod 2Gene Regulates Gamma Interferon Production of NK Cells in Host Response to Lipopolysaccharide-Induced Endotoxic Shock

The Circadian ClockPeriod 2Gene Regulates Gamma Interferon Production of NK Cells in Host Response to Lipopolysaccharide-Induced Endotoxic Shock

Resistance of the Brain to Escherichia coli K1 Infection Depends on MyD88 Signaling and the Contribution of Neutrophils and Monocytes

Immunobiology of the blood-brain barrier

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