Leukemia inhibitory factor, a cytokine at the interface between neurobiology and immunology.

Patterson, Paul H.

doi:10.1073/pnas.91.17.7833

Cited by 115 publications

(62 citation statements)

References 86 publications

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“…[192][193][194] LIF is produced as a component of the host response to inflammatory stimuli and is an early mediator of the inflammatory cytokine response. Serum levels of LIF rise progressively during lethal endotoxic shock in mice, and prior administration of LIF protects against lethality in a dose-and time-dependent manner.…”

Section: 161177178mentioning

confidence: 99%

Review: Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis

Beishuizen

Thijs

2003

Journal of Endotoxin Research

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Endotoxin is considered to be a systemic (immunological) stressor eliciting a prolonged activation of the hypothalamo-pituitary-adrenal (HPA) axis. The HPA-axis response after an endotoxin challenge is mainly due to released cytokines (IL-1, IL-6 and TNF-a) from stimulated peripheral immune cells, which in turn stimulate different levels of the HPA axis. Controversy exists regarding the main locus of action of endotoxin on glucocorticoid secretion, since the effect of endotoxin on this neuro-endocrine axis has been observed in intact animals and after ablation of the hypothalamus; however, a lack of LPS effect has been described at both pituitary and adrenocortical levels. The resulting increase in adrenal glucocorticoids has well-documented inhibitory effects on the inflammatory process and on inflammatory cytokine release. Therefore, immune activation of the adrenal gland by endotoxin is thought to occur by cytokine stimulation of corticosteroidreleasing hormone (CRH) production in the median eminence of the hypothalamus, which, in turn stimulates the secretion of ACTH from the pituitary. Acute administration of endotoxin stimulates ACTH and cortisol secretion and the release of CRH and vasopressin (AVP) in the hypophysial portal blood. During repeated endotoxemia, tolerance of both immune and HPA function develops, with a crucial role for glucocorticoids in the modulation of the HPA axis. A single exposure to a high dose of LPS can induce a long-lasting state of tolerance to a second exposure of LPS, affecting the response of plasma TNF-a and HPA hormones. Although there are gender differences in the HPA response to endotoxin and IL-1, these responses are enhanced by castration and attenuated by androgen and estrogen replacement. Estrogens attenuate the endotoxin-induced stimulation of IL-6, TNF-a and IL-1ra release and subsequent activation in postmenopausal women. There appears to be a temporal and functional relation between the HPA-axis response to endotoxin and nitric oxide formation in the neuro-endocrine hypothalamus, suggesting a stimulatory role for nitric oxide in modulating the HPA response to immune challenges. demonstrate higher plasma levels of IL-1 and TNF-a. Elevation of plasma glucocorticoids results in suppression of cytokines such as IL-1, IL-6, and TNF-a and in up-regulation of other cytokines, such as IL-4 and IL-10, and cytokine receptors. Thus, by regulation of cytokine production and action, the HPA axis contributes to modulation of the response to inflammation/infection. In addition, the role of HPA activation has been suggested to be a negative feedback system provided by the immunosuppressive activity of glucocorticoids, limiting inflammatory responses and preventing the immune system from over-reacting and causing tissue damage or autoimmunity.As early as 1957, Wexler et al. suggested that LPS could induce ACTH release since they found a depletion of ascorbic acid and cholesterol in the adrenal glands. 10 Moreover, LPS was not able to cause these changes in hypophysectomized rats. ...

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Section: 161177178mentioning

confidence: 99%

Review: Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis

Beishuizen

Thijs

2003

Journal of Endotoxin Research

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“…Over the last 20 years, a number of investigators have demonstrated interactions between the immune and neural systems during normal organismal development (Patterson, 1994;Armstrong et al, 2003;Siemion et al, 2005;Wrona, 2006). Our laboratories have been investigating proteins that regulate innervation during the earliest stages of inner ear development (reviewed by Barald and Kelley, 2004;Gerlach et al, 2000), and our recent work highlights the importance of chemokines and cytokines in the early stage peripheral auditory system (Bianchi et al, 2005;Holmes et al, 2011;Shen et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Macrophage migration inhibitory factor acts as a neurotrophin in the developing inner ear

et al. 2012

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This study is the first to demonstrate that macrophage migration inhibitory factor (MIF), an immune system ‘inflammatory’ cytokine that is released by the developing otocyst, plays a role in regulating early innervation of the mouse and chick inner ear. We demonstrate that MIF is a major bioactive component of the previously uncharacterized otocyst-derived factor, which directs initial neurite outgrowth from the statoacoustic ganglion (SAG) to the developing inner ear. Recombinant MIF acts as a neurotrophin in promoting both SAG directional neurite outgrowth and neuronal survival and is expressed in both the developing and mature inner ear of chick and mouse. A MIF receptor, CD74, is found on both embryonic SAG neurons and adult mouse spiral ganglion neurons. Mif knockout mice are hearing impaired and demonstrate altered innervation to the organ of Corti, as well as fewer sensory hair cells. Furthermore, mouse embryonic stem cells become neuron-like when exposed to picomolar levels of MIF, suggesting the general importance of this cytokine in neural development.

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“…Upon binding to its heterodimeric receptor formed by gp130 (IL6ST) and LIFR, LIF elicits a cascade of signaling events mediated through JAK-STAT3 (Janus kinase-Signal transducer and activator of transcription 3), MEK (MAPK/ERK kinase), and PI3K (phosphoinositide 3-kinases) pathways [9]. These pathways are primarily associated with cell survival, differentiation, and regulation of apoptosis, respectively, in non-neural stem cells, such as mouse ESCs [10].…”

Section: Introductionmentioning

confidence: 99%

Neurotrophic Effects of Leukemia Inhibitory Factor on Neural Cells Derived from Human Embryonic Stem Cells

et al. 2012

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Various growth factor cocktails have been used to proliferate and then differentiate human neural progenitor (NP) cells derived from embryonic stem cells (ESC) for in vitro and in vivo studies. However, the cytokine leukemia inhibitory factor (LIF) has been largely overlooked. Here, we demonstrate that LIF significantly enhanced in vitro survival and promoted differentiation of human ESC-derived NP cells. In NP cells, as well as NP-derived neurons, LIF reduced caspase-mediated apoptosis and reduced both spontaneous and H 2 O 2 -induced reactive oxygen species in culture. In vitro, NP cell proliferation and the yield of differentiated neurons were significantly higher in the presence of LIF. In NP cells, LIF enhanced cMyc phosphorylation, commonly associated with self-renewal/proliferation. Also, in differentiating NP cells LIF activated the phosphoinositide 3-kinase and signal transducer and activator of transcription 3 pathways, associated with cell survival and reduced apoptosis. When differentiated in LIF 1 media, neurite outgrowth and ERK1/2 phosphorylation were potentiated together with increased expression of gp130, a component of the LIF receptor complex. NP cells, pretreated in vitro with LIF, were effective in reducing infarct volume in a model of focal ischemic stroke but LIF did not lead to significantly improved initial NP cell survival over nontreated NP cells. Our results show that LIF signaling significantly promotes human NP cell proliferation, survival, and differentiation in vitro. Activated LIF signaling should be considered in cell culture expansion systems for future human NP cell-based therapeutic transplant studies.

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Leukemia inhibitory factor, a cytokine at the interface between neurobiology and immunology.

Cited by 115 publications

References 86 publications

Review: Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis

Review: Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis

Macrophage migration inhibitory factor acts as a neurotrophin in the developing inner ear

Neurotrophic Effects of Leukemia Inhibitory Factor on Neural Cells Derived from Human Embryonic Stem Cells

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