Opposing effects of pituitary leukemia inhibitory factor and SOCS-3 on the ACTH axis response to inflammation

2002 ◽  
Vol 282 (5) ◽  
pp. E1110-E1118 ◽  
Author(s):  
Vera Chesnokova ◽  
Anastasia Kariagina ◽  
Shlomo Melmed
Keyword(s):  
Hpa Axis ◽  
Leukemia Inhibitory Factor ◽  
Inflammatory Responses ◽  
Inhibitory Factor ◽  
Cytokine Signaling ◽  
Amyloid A ◽  
Tnf Α ◽  
Factor Α ◽  
Opposing Effects

We have shown that leukemia inhibitory factor (LIF) and suppressor of cytokine signaling (SOCS)-3 are expressed in the hypothalamus and pituitary and that LIF induces proopiomelanocortin (POMC) and ACTH, whereas SOCS-3 abrogates corticotroph POMC gene transcription and ACTH secretion. Here, we determined the role of pituitary LIF and SOCS-3 in regulating hypothalamo-pituitary-adrenal (HPA) axis inflammatory responses. Murine pituitary LIF expression was induced up to eightfold after intraperitoneal injection of lipopolysaccharide or tumor necrosis factor-α, concordant with elevated plasma levels of ACTH and corticosterone. In LIF knockout (LIFKO) mice, induction of both ACTH and corticosterone were attenuated. LIF deletion was associated with elevated ( P < 0.05) levels of pituitary TNF-α, interleukin (IL)-1β, and IL-6 mRNA and cytokine-inducible pituitary SOCS-3 expression. Abrogation of the HPA axis stress response and higher pituitary levels of proinflammatory cytokines observed in LIFKO mice resulted in a stronger inflammatory process, as evidenced by elevated erythrocyte sedimentation rate and increased serum amyloid A levels ( P < 0.05). The results indicate that, although LIF induces ACTH, SOCS-3 acts to counterregulate the HPA axis response to inflammation.

Leukemia inhibitory factor regulates glucocorticoid receptor expression in the hypothalamic-pituitary-adrenal axis

2005 ◽  
Vol 289 (5) ◽  
pp. E857-E863 ◽  
Author(s):  
Anastasia Kariagina ◽  
Svetlana Zonis ◽  
Mahta Afkhami ◽  
Dmitry Romanenko ◽  
Vera Chesnokova
Keyword(s):  
Glucocorticoid Receptor ◽  
Hpa Axis ◽  
Leukemia Inhibitory Factor ◽  
Dominant Negative ◽  
Receptor Expression ◽  
Inhibitory Factor ◽  
Mrna Levels ◽  
Hypothalamic Pituitary Adrenal ◽  
Protein Levels

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine belonging to the gp130 family. LIF is induced peripherally and within the brain during inflammatory or chronic autoimmune diseases and is a potent stimulator of the hypothalamic-pituitary-adrenal (HPA) axis. Here we investigated the role of LIF in mediating glucocorticoid receptor (GR) expression in the HPA axis. LIF treatment (3 μg/mouse, ip) markedly decreased GR mRNA levels in murine hypothalamus (5-fold, P < 0.01) and pituitary (1.7-fold, P < 0.01) and downregulated GR protein levels. LIF decreased GR expression in murine corticotroph cell line AtT20 within 2 h, and this effect was sustained for 8 h after treatment. LIF-induced GR mRNA reduction was abrogated in AtT20 cells overexpressing dominant-negative mutants of STAT3, indicating that intact JAK-STAT signaling is required to mediate LIF effects on GR expression. Conversely, mice with LIF deficiency exhibited increased GR mRNA levels in the hypothalamus and pituitary (3.5- and 3.5-fold, respectively; P < 0.01 for both) and increased GR protein expression when compared with wild-type littermates. The suppressive effects of dexamethasone on GR were more pronounced in LIF-null animals. These data suggest that LIF maintains the HPA axis activation by decreasing GR expression and raise the possibility that LIF might contribute to the development of central glucocorticoid resistance during inflammation.

scholarly journals Serum amyloid A overrides Treg anergy via monocyte-dependent and Treg-intrinsic, SOCS3-associated pathways

Blood ◽  
2011 ◽  
Vol 117 (14) ◽  
pp. 3793-3798 ◽  
Author(s):  
Khoa D. Nguyen ◽  
Claudia Macaubas ◽  
Kari C. Nadeau ◽  
Phi Truong ◽  
Taejin Yoon ◽  
...  
Keyword(s):  
T Cells ◽  
Serum Amyloid A ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Serum Amyloid ◽  
Cytokine Signaling ◽  
Amyloid A ◽  
Inflammatory Processes ◽  
Anti Inflammatory

Abstract The acute phase protein serum amyloid A (SAA) has been well characterized as an indicator of inflammation. Nevertheless, its functions in pro versus anti-inflammatory processes remain obscure. Here we provide unexpected evidences that SAA induces the proliferation of the tolerogenic subset of regulatory T cells (Treg). Intriguingly, SAA reverses Treg anergy via its interaction with monocytes to activate distinct mitogenic pathways in Treg but not effector T cells. This selective responsiveness of Treg correlates with their diminished expression of SOCS3 and is antagonized by Treg–specific induction of this regulator of cytokine signaling. Collectively, these evidences suggest a novel anti-inflammatory role of SAA in the induction of a micro-environment that supports Treg expansion at sites of infection or tissue injury, likely to curb (auto)-inflammatory responses.

scholarly journals Intestinal epithelial suppressor of cytokine signaling 3 enhances microbial-induced inflammatory tumor necrosis factor-α, contributing to epithelial barrier dysfunction

2015 ◽  
Vol 308 (1) ◽  
pp. G25-G31 ◽  
Author(s):  
Imtiyaz Thagia ◽  
Elisabeth J. Shaw ◽  
Emily Smith ◽  
Kathryn J. Else ◽  
Rachael J. Rigby
Keyword(s):  
Wound Healing ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Cytokine Signaling ◽  
Intestinal Epithelial ◽  
Suppressor Of Cytokine Signaling ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

A single layer of intestinal epithelial cells (IEC) lines the entire gastrointestinal tract and provides the first line of defense and barrier against an abundance of microbial stimuli. IEC homeostasis and repair are mediated through microbe-sensing Toll-like receptor (TLR)-induced inflammatory pathways. Increasing evidence supports a role of suppressor of cytokine signaling 3 (SOCS3) as a modulator of IEC turnover, balancing controlled repair and replenishment with excessive IEC proliferation predisposing to dysplasia and cancer. Our data indicate that SOCS3 can limit microbial-induced IEC repair, potentially through promoting tumor necrosis factor-α (TNF-α) and limiting TNFR2 expression. Activation of TLR5 signaling pathways, compared with other TLR, increases TNF-α mRNA in a dose-dependent manner and SOCS3 enhances TLR5-induced TNF-α. We also show that flagellin promotes transcription of TNFR2 and that SOCS3 limits this expression, presenting a mechanism of SOCS3 action. Our data also support the role of microbial ligands in epithelial wound healing and suggest that a functional consequence of increased TNF-α is reduced wound healing. These results provide further evidence to support the regulatory role of epithelial SOCS3 in intestinal health and suggest that the increased expression of SOCS3 observed in IBD may serve to perpetuate “inflammation” by promoting TNF-α production and limiting epithelial repair in response to commensal microflora.

scholarly journals Absence of suppressor of cytokine signaling 2 turns cardiomyocytes unresponsive to LIF-dependent increases in Ca2+ levels

2017 ◽  
Vol 312 (4) ◽  
pp. C478-C486 ◽  
Author(s):  
Cibele Rocha-Resende ◽  
Itamar Couto Guedes de Jesus ◽  
Danilo Roman-Campos ◽  
Artur S. Miranda ◽  
Fabiana Alves ◽  
...  
Keyword(s):  
Leukemia Inhibitory Factor ◽  
Inhibitory Factor ◽  
Cytokine Signaling ◽  
Wild Type ◽  
Suppressor Of Cytokine Signaling ◽  
Gp130 Receptor ◽  
Intracellular Ca ◽  
Full Activation

Little is known regarding the role of suppressor of cytokine signaling (SOCS) in the control of cytokine signaling in cardiomyocytes. We investigated the consequences of SOCS2 ablation for leukemia inhibitory factor (LIF)-induced enhancement of intracellular Ca2+ ([Ca2+]i) transient by performing experiments with cardiomyocytes from SOCS2-knockout (ko) mice. Similar levels of SOCS3 transcripts were seen in cardiomyocytes from wild-type and SOCS2-ko mice, while SOCS1 mRNA was reduced in SOCS2-ko. Immunoprecipitation experiments showed increased SOCS3 association with gp130 receptor in SOCS2-ko myocytes. Measurements of Ca2+ in wild-type myocytes exposed to LIF showed a significant increase in the magnitude of the Ca2+ transient. This change was absent in LIF-treated SOCS2-ko cells. LIF activation of ERK and STAT3 was observed in both wild-type and SOCS2-ko cells, indicating that in SOCS2-ko, LIF receptors were functional, despite the lack of effect in the Ca2+ transient. In wild-type cells, LIF-induced increase in [Ca2+]i and phospholamban Thr17 [PLN(Thr17)] phosphorylation was inhibited by KN-93, indicating a role for CaMKII in LIF-induced Ca2+ raise. LIF-induced phosphorylation of PLN(Thr17) was abrogated in SOCS2-ko myocytes. In wild-type cardiomyocytes, LIF treatment increased L-type Ca2+ current ( ICa,L), a key activator of CaMKII in response to LIF. Conversely, SOCS2-ko myocytes failed to activate ICa,L in response to LIF, providing a rationale for the lack of LIF effect on Ca2+ transient. Our data show that absence of SOCS2 turns cardiomyocytes unresponsive to LIF-induced [Ca2+] raise, indicating that endogenous levels of SOCS2 are crucial for full activation of LIF signaling in the heart.

scholarly journals Macrophage Migration Inhibitory Factor in Vitiligo: Pathogenesis and Potential Therapeutic Aspects

2021 ◽  
pp. 8-24
Author(s):  
Hassan Mohammed Ibrahim ◽  
Essam El-din Abd El-Aziz Nada ◽  
Soheir Abdel-Hamid Ali ◽  
Eisa Mohamed Hegazy ◽  
Mohammed H. Hassan
Keyword(s):  
Treatment Guidelines ◽  
Inflammatory Responses ◽  
Skin Pigmentation ◽  
Inhibitory Factor ◽  
Immunomodulatory Agents ◽  
Proinflammatory Mediators ◽  
Systemic Corticosteroids ◽  
Gradual Loss ◽  
Tnf Α

Vitiligo is an acquired skin disorder that is characterized by a gradual loss of skin pigmentation when melanocytes, the skin's pigment-producing cellsis lost. Pathogenicmechanisms are not well understood. Genetic, abnormal biochemical pathways, autoimmune, melanocyte adhesion deficits and nervous system imbalances are among the pathogenic triggers. Vitiligo lesions have  also been shown to have macrophage infiltration.Macrophagemigration inhibitory factor (MIF) is a lymphokine that concentrates macrophages at inflammatory sites and is involved in cell-mediated immunity.MIF enhances chemotaxis and macrophage infiltration and upregulates inflammatory responses by inducing the expression of proinflammatory mediators such as TNF-α, nitric oxide and prostaglandin E2.Therapyfor vitiligo includes corticosteroids, immunomodulatory agents, vitamin D nalogues, antioxidants, phototherapy, laser and surgical therapy.However, no single treatment for vitiligo produces consistently good results and treatment response is variable.  Narrow-band ultraviolet (NB-UVB, 311–313nm) phototherapy is viewed as backbone of treatment. Systemic therapies such as systemic corticosteroids and methotrexate were previously used to treat vitiligo which was assumed to be auto-immune nature.Pathogenic mechanisms, role of MIF and various treatment guidelines are discussed in this review

scholarly journals Manipulation of Quercetin and Melatonin in the Down-Regulation of HIF-1α, HSP-70 and VEGF Pathways in Rat’s Kidneys Induced by Hypoxic Stress

Dose-Response ◽  
2020 ◽  
Vol 18 (3) ◽  
pp. 155932582094979
Author(s):  
Aliah R. Alshanwani ◽  
Sameerah Shaheen ◽  
Laila M. Faddah ◽  
Ahlam M. Alhusaini ◽  
Hanaa M. Ali ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Histopathological Examination ◽  
Hemoglobin Concentration ◽  
Vascular Endothelial ◽  
Hsp 70 ◽  
Reactive Protein ◽  
Defensive Role ◽  
Factor Α ◽  
Endothelial Growth Factor

Hypoxia may lead to inflammatory responses by numerous signaling pathways. This investigation intended to inspect the defensive role of Quercetin (Quer) and/ or Melatonin (Mel) against reno toxicity induced by Sodium nitrite (Sod ntr). Sod ntr injection significantly decreased blood hemoglobin concentration (Hb) with a concurrent increase in serum tumor necrosis factor- α, interleukin-6, C-reactive protein, creatinine, and urea levels. Over protein-expression of vascular endothelial growth factor and heat shock, protein-70 and mRNA of HIF-1α were also observed. Pretreatment of the Sod ntr- injected rats with the aforementioned antioxidants; either alone or together significantly improved such parameters. Histopathological examination reinforced the previous results. It was concluded that the combined administration of Quer and Mel may be useful as a potential therapy against renal injury induced by Sod ntr. HIF-1α and HSP-70 are implicated in the induction of hypoxia and its treatment.

scholarly journals Astrocytes and neuroinflammation in Alzheimer's disease

2014 ◽  
Vol 42 (5) ◽  
pp. 1321-1325 ◽  
Author(s):  
Emma C. Phillips ◽  
Cara L. Croft ◽  
Ksenia Kurbatskaya ◽  
Michael J. O’Neill ◽  
Michael L. Hutton ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inflammatory Responses ◽  
Amyloid Β ◽  
Synaptic Dysfunction ◽  
Amyloid Β Peptide ◽  
Substantial Evidence ◽  
Models Of Disease ◽  
Opposing Effects

Increased production of amyloid β-peptide (Aβ) and altered processing of tau in Alzheimer's disease (AD) are associated with synaptic dysfunction, neuronal death and cognitive and behavioural deficits. Neuroinflammation is also a prominent feature of AD brain and considerable evidence indicates that inflammatory events play a significant role in modulating the progression of AD. The role of microglia in AD inflammation has long been acknowledged. Substantial evidence now demonstrates that astrocyte-mediated inflammatory responses also influence pathology development, synapse health and neurodegeneration in AD. Several anti-inflammatory therapies targeting astrocytes show significant benefit in models of disease, particularly with respect to tau-associated neurodegeneration. However, the effectiveness of these approaches is complex, since modulating inflammatory pathways often has opposing effects on the development of tau and amyloid pathology, and is dependent on the precise phenotype and activities of astrocytes in different cellular environments. An increased understanding of interactions between astrocytes and neurons under different conditions is required for the development of safe and effective astrocyte-based therapies for AD and related neurodegenerative diseases.

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