Influence Of Proinflammatory Cytokines Research Articles

ROLE OF PROINFLAMMATORY CYTOKINES IN CHRONIC HEART FAILURE

Accumulating evidence indicates that cytokines play an important role in the pathogenesis of chronic heart failure. The review considers the participation of proinflammatory cytokines (factors-necroses-tumors-α, interleukin 1β and interleukin 6) in the pathophysiological processes of congestive heart failure, as well as the influence of proinflammatory cytokines on cardiac contractility, hypertrophy and remodeling of the left ventricle of the heart, apoptotic, and fibrotic processes.

HIV, depression and compliance: the mediating role of cytokines. A review of the international literature

HIV-positive individuals are at greater risk of depression, which is known to influence their well-being negatively. In fact, depression may promote unhealthy behaviors (e.g. drug use and intentional unprotected sex); furthermore, depression may also act reducing immune system functioning. However, the relationship between the immune system and depression is bidirectional, since many physchoneuroimmunological research studies have shown that immune system activation, more specifically pro-inflammatory cytokines, increases the risk of depression. Thus, HIV-positive persons with co-infection (e.g. HCV), taking HAART and/or interferon-α, may show cytokine dysregulation. This may explain the greater prevalence of depression among HIV-positive individuals. In fact, pro-inflammatory cytokines and cortisol (also known as stress hormone), both promote tryptophan depletion, which is commonly associated with depressive symptoms. Hence, depression may negatively influence compliance, increasing the risk for incorrect assumption of antiretroviral leading to a significant reduction of immune system functioning. This review examines the relationship between HIV infection, co-infection (e.g., HCV), HAART and/or interferon-α therapy and cytokine dysregulation, with a focus on the influence of pro-inflammatory cytokines in promoting depression, which could ultimately reduce compliance. Evidence-based pharmacological and psycho-social interventions on depression are also discussed.

Osteoimmunology and the influence of pro-inflammatory cytokines on osteoclasts

Bone and immune system are functionally interconnected. Immune and bone cells derive from same progenitors in the bone marrow, they share a common microenvironment and are being influenced by similar mediators. The evidence on increased bone resorption associated with inappropriate activation of T cells such as during inflammation, is well established. However, the molecular mechanisms beyond this clinical observation have begun to be intensively studied with the advancement of osteoimmunology. Now days, we have firm evidence on the influence of numerous proinflammatory cytokines on bone cells, with the majority of data focused on osteoclasts, the bone resorbing cells. It has been shown that some proinflammatory cytokines could possess osteoclastogenic and/or anti-osteoclastogenic properties and can target osteoclasts directly or via receptor activator of nuclear factor κB (RANK)/RANK ligand(RANKL)/osteoprotegerin (OPG) system. Several studies have reported opposing data regarding (anti)osteoclastogenic properties of these cytokines.Therefore, the first part of this review is summarizing current evidence on the influence of pro-inflammatory cytokines on osteoclasts and thus on bone resorption. In the second part, the evidence on the role of pro-inflammatory cytokines in osteoporosis and osteoarthritis is reviewed to show that unravelling the mechanisms beyond such complex bone diseases, is almost impossible without considering skeletal and immune systems as an indivisible integrated system.

Accumulation of Gr-1dim myeloid-derived suppressor cells during experimental TB infection in mice

Event Abstract Back to Event Accumulation of Gr-1dim myeloid-derived suppressor cells during experimental TB infection in mice Evgeny N. Tsiganov1*, Alyona M. Razinkova1 and Iirina V. Lyadova1 1 Central Research Institute of Tuberculosis, Russian Academy of Medical Sciences, Immunology, Russia Severe TB infection is characterized by excessive inflammation and impaired T-cell responses. How these two features are interrelated is poorly understood. Earlier we revealed, that experimental TB in mice is associated with the accumulation of unusual Gr-1dim CD11b+ cells. The role of these cells during TB is unknown. However, in cancer researches it was established, that similar cell population can be induced under the influence of pro-inflammatory cytokines, suppress T-cell responses and is named myeloid-derived suppressor cells (MDSC). Considering the peculiarities of TB progression, we suggested that Gr-1dim cells, accumulating during TB may represent MDSC and influence TB outcome. To test this assumption we studied dynamics, characteristics and possible role of Gr-1dim cells during TB. We found out that Gr-1dim cells were rare in un-infected mice, but accumulated in lungs, bone marrow and blood of infected mice during TB progression reaching their maximum (30 - 40%) at the prelethal stage of infection. These cells co-expressed monocytic (F4/80+) and granulocytic (Ly-6Gdim) markers and had mononuclear morphology, thus, displaying the phenotype of immature myeloid cells. Further we revealed that magnetically sorted Gr-1dim cells suppressed proliferation of anti-CD3-stimulated T-cells and their IFN-γ production. The suppressive activity of Gr-1dim cells was mediated by NO-dependent mechanism and required cell-to-cell interactions with target cells. Thus, here we report the accumulation of MDSC during TB infection. This may represent the new mechanism of TB progression and may also be helpful in disease monitoring or therapy development in future. Keywords: Tuberculosis, MDSC, Gr-1dim, Neutrophils, NO Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Host-pathogen interactions Citation: Tsiganov EN, Razinkova AM and Lyadova IV (2013). Accumulation of Gr-1dim myeloid-derived suppressor cells during experimental TB infection in mice. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00220 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 12 Mar 2013; Published Online: 22 Aug 2013. * Correspondence: Mr. Evgeny N Tsiganov, Central Research Institute of Tuberculosis, Russian Academy of Medical Sciences, Immunology, Moscow, Russia, student57@rambler.ru Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Evgeny N Tsiganov Alyona M Razinkova Iirina V Lyadova Google Evgeny N Tsiganov Alyona M Razinkova Iirina V Lyadova Google Scholar Evgeny N Tsiganov Alyona M Razinkova Iirina V Lyadova PubMed Evgeny N Tsiganov Alyona M Razinkova Iirina V Lyadova Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Extracellular factors and immunosuppressive drugs influencing insulin secretion of murine islets

Approximately 60% of transplanted islets undergo apoptosis within the first week post-transplantation into the liver attributed to poor engraftment, immune rejection and toxicity of immunosuppressive drugs. Understanding how extracellular matrix (ECM) components, immunosuppressive drugs and proinflammatory cytokines affect insulin secretion will contribute to an improved clinical outcome of islet transplantations. In this study, functional activity of isolated murine islets was measured by glucose-stimulated insulin secretion (GSIS) and by electrophysiological measurements using patch-clamp. Cultivating islets with soluble fibronectin or laminin, as opposed to with coated laminin, markedly increased GSIS. Addition of cyclosporin A reduced GSIS and suppressed glucose-induced spike activity. Tacrolimus affected neither GSIS nor spike activity, indicating a different mechanism. To evaluate the influence of proinflammatory cytokines, islets were incubated with interleukin (IL)-1β, tumour necrosis factor (TNF)-α or with supernatants from cultured Kupffer cells, the main mediators of inflammation in the hepatic sinusoids. IL-1β exerted a bimodal effect on insulin secretion, stimulating below 2 ng/ml and suppressing above 10 ng/ml. Soluble laminin in combination with a stimulatory IL-1β concentration further increased insulin secretion by 20% compared to IL-1β alone, while with high IL-1β concentrations soluble laminin slightly attenuated GSIS inhibition. TNF-α alone did not affect GSIS, but with stimulatory IL-1β concentrations completely abolished it. Similarly, supernatants derived from Kupffer cells exerted a bimodal effect on GSIS. Our data suggest that improved insulin secretion of transplanted islets could be achieved by including soluble laminin and low IL-1β concentrations in the islet cultivation medium, and by a simultaneous inhibition of cytokine secretion from Kupffer cells.

Rod-Shaped Monocytes Patrol the Brain Vasculature and Give Rise to Perivascular Macrophages under the Influence of Proinflammatory Cytokines and Angiopoietin-2

The nervous system is constantly infiltrated by blood-derived sentinels known as perivascular macrophages. Their immediate precursors have not yet been identified in situ and the mechanism that governs their recruitment is mostly unknown. Here, we provide evidence that CD68(+)GR1(-) monocytes can give rise to perivascular macrophages in mice suffering from endotoxemia. After adhesion to the endothelium, these monocytes start to crawl, adopt a rod-shaped morphology when passing through capillaries, and can manifest the ability to proliferate and form a long cytoplasmic protuberance. They are attracted in greater numbers during endotoxemia by a combination of vasoregulatory molecules, including TNF (tumor necrosis factor), interleukin-1beta, and angiopoietin-2. After a period of several hours, some of them cross the endothelium to expand the population of perivascular macrophages. Depletion of adherent monocytes and perivascular macrophages can be achieved by injection of anti-angiopoietin-2 peptide-Fc fusion protein. This study extends our understanding of the behavior of monocytes at the blood-brain interface and provides a way to block their infiltration into the nervous tissue under inflammatory conditions.

Non-termination of sickness behavior as precipitating factor for mental disorders

Sickness behavior can be defined as a combination of coordinated behavioral and physiological changes that develop in response to any condition that elicits pro-inflammatory activity. It is an adaptational homeostasis initiated by the influence of pro-inflammatory cytokines on central nervous system neurohormonal functioning. This paper introduces the concept of non-termination of sickness behavior as a potential threat to mental health. In view of the similarities between the behavioral symptoms, the neuroendocrine and the cytokine profiles of sickness behavior and that of a number of mental disorders it is hypothesized that the inappropriate continuation of sickness behavior, (i.e., non-termination), after recovery from the initial disease, could form the basis for mental disturbances. This would be particularly relevant in individuals with alterations in stress vulnerability (altered activation threshold and impaired negative feedback), which may occur due to the combination of genetic disposition and priming by early life experiences.

Influence of proinflammatory cytokines on the adhesion of human colon carcinoma cells to lung microvascular endothelium.

In this experimental study, the influence of surgery-induced proinflammatory cytokines on tumor recurrence in the lung was investigated. A reproducible human in vitro assay was developed to study the adhesion of HT29 colon carcinoma cells to monolayers of microvascular endothelial cells of the lung (HMVECs-L) or human umbilical venous endothelial cells (HUVECs). Preincubation of HMVECs-L with maximally active concentrations of IL-1beta and TNF-alpha, but not with IL-6, resulted in at least 250% adhesion compared to control adhesion (p <or= 0.01). The effect of IL-1beta and TNF-alpha was concentration- and time-dependent. Comparable results were found for HUVECs. Tumor cell adhesion was not increased after preincubation of HT29 with TNF-alpha. Enzyme immunoassays of cytokine-preincubated HUVECs and HMVECs-L showed concentration- and time-dependent upregulation of E-selectin, ICAM-1 and VCAM-1 expression. In addition, LFA-1 and VLA-4 were only expressed on HMVECs-L, creating more binding possibilities for HMVECs-L compared to HUVECs. Inhibition assays with anti-E-selectin monoclonal antibody significantly decreased tumor cell adhesion to HUVECs; however, it did not affect tumor cell adhesion to HMVECs-L. Furthermore, anti-ICAM-1 and anti-VCAM-1 antibodies did not affect adhesion. Our results prove IL-1beta and TNF-alpha promote tumor cell adhesion to HMVECs-L in vitro and may therefore account for enhanced tumor recurrence in the lung seen after major surgical trauma. The adhesion of HT29 to HUVEC is inhibitable by E-selectin antibodies, whereas the adhesion to HMVEC-L is not inhibitable by these antibodies. Probably not one but a complex of adhesion molecules is responsible for enhanced adhesion to HMVECs-L.

Down-regulation of alpha class glutathione S-transferase by interleukin-1beta in human intestinal epithelial cells (Caco-2) in culture.

The influence of pro-inflammatory cytokines on alpha class glutathione S-transferase A1 and A2 (GSTA1/A2) expression was examined in human colonic epithelial cells (Caco-2) in culture. Dose-dependent reductions in GSTA1/A2 mRNA, protein, and activity levels occurred in Caco-2 cells cultured in conditioned medium (CM) from lipopolysaccharide-stimulated murine monocyte-macrophage cells (RAW 264.7). Neutralizing anti-interleukin-1beta (IL-1beta) antibodies attenuated this repression of GSTA1/A2 expression by CM. Moreover, recombinant human IL-1beta reduced GSTalpha expression at the mRNA, protein, and activity levels in a dose-related fashion. Reduction of GSTA1/A2 mRNA levels by IL-1beta was attenuated by pretreatment with IL-1 receptor antagonist. GSTA1/A2 mRNA half-lives were similar in control and IL-1beta-treated cells, indicating that IL-1beta has no effect on mRNA stability. In reporter gene studies, IL-1beta caused a dose-related reduction of luciferase activity in Caco-2 cells transfected with the full-length GSTA1 promoter-luciferase construct. Using truncated constructs, IL-1beta responsiveness was mapped to a region 286 base pairs upstream to the coding region. Deletion of a hepatic nuclear factor 1 (HNF-1) site in this region abrogated the IL-1beta-mediated repression of GSTA1 promoter activity. These results demonstrate that IL-1beta down-regulates GSTA1/A2 expression in cultured human enterocytes by a transcriptional mechanism involving an HNF-1 site.

The influence of pro-inflammatory cytokines on human retinal pigment epithelium cell receptors.

To investigate the mRNA expression of the receptors for tumour necrosis factor alpha (TNFRp55, TNFRp75), interferon gamma (IFN gamma R alpha, IFN gamma R beta), interleukin 10 (IL-10R, CRFB4) and transforming growth factor beta (TGF beta RII) on human retinal pigment epithelium (RPE) cells and to modulate this expression with the pro-inflammatory cytokines TNF-alpha and IFN-gamma as stimulators. The cells were cultured in the presence of TNF-alpha (10 ng/ml), IFN-gamma (1000 U/ml) or a combination of both for 24 h, 48 h and 72 h. The total RNA was prepared, and the receptor mRNA expression was investigated by the reverse-transcription polymerase chain reaction method. The changes in mRNA expression during the modulation were quantified by the ribonuclease protection assay. The mRNA for TNFRp55, TNFRp75, IFN gamma R alpha, IFN gamma R beta, CRFB4 and TGF beta RII was constitutively expressed in vitro. IL-10R mRNA was detected in neither unstimulated nor stimulated RPE cells. Especially the mRNA of the TNF-Rp75 was up-regulated, mainly by IFN-gamma or the combination of both stimulators. Our results demonstrate that human RPE cells express the mRNA of different cytokine receptors and the expression may be partially modulated by pro-inflammatory cytokines. This may show that RPE cells act as corresponding cells not only in vitro, but also in inflammation and immunological processes in the eye. In this connection it could be hypothesised that activated RPE cells play a stimulating role in addition to the known suppressive one.

Suppressive effect of zinc ion on iNOS expression induced by interferon-γ or tumor necrosis factor-α in murine keratinocytes

Zinc, an essential metal, is a critical component of zinc binding proteins such as zinc fingers, zinc enzymes and metallothioneins. Recently, evidence for its anti-inflammatory property in skin has been accumulating, as shown in the treatment of acne, alopecia and zinc deficiency. In cutaneous inflammations, a large amount of nitric oxide (NO) is produced through induction of inducible nitric oxide synthase (iNOS) under the influence of proinflammatory cytokines, resulting in tissue damages in skin, as clarified in other organs. Therefore, we asked if the effect of zinc on NO production and/or on iNOS expression in keratinocytes may explain the anti-inflammatory property of zinc in skin. Accordingly, we sought to determine in this study whether zinc ion may have effect on IFN-γ or TNF-α induced NO production and iNOS expression in cultured murine keratinocytes. Ten μM of zinc ion remarkably suppressed cytokine-induced NO production in keratinocytes. Furthermore, zinc ion also suppressed cytokine-induced iNOS expression in the protein level as well as in the messenger RNA level. These results suggest the possibility that the suppressive effect of zinc ion on cytokine-induced NO production in keratinocytes may be in part implicated in the anti-inflammatory property of zinc in some of skin disorders.

Cytokines increase endothelin ETB receptor contractile activity in rat cerebral artery.

The plasticity of endothelin ETB receptor activity and the influence of pro-inflammatory cytokines was examined in cerebral artery. In fresh rat basilar artery, the selective ETB receptor agonist, sarafotoxin S6c, induced negligible contractions. However, after 1 day of organ culture, fully defined concentration-response curves were obtained in artery segments exposed to sarafotoxin S6c. Organ culture in the presence of either interleukin-1 beta or tumour necrosis factor-alpha, but not interleukin-2 or interleukin-6, further amplified the maximal contraction to sarafotoxin S6c. The plasticity of ETB receptor expression in cerebral arteries and sensitivity for pro-inflammatory cytokines, suggest a role in inflammatory cerebral diseases such as stroke.

Transferrin-iron and proinflammatory cytokines influence iron status and apical iron transport efficiency of Caco-2 intestinal cell line

Endogenous factors that regulate the absorption of dietary iron remain unknown. Differentiated cultures of Caco-2 human intestinal cells grown on membrane inserts were used to study the characteristics of transferrin-iron uptake across the basolateral surface, the effects of transferrin-iron uptake on cellular ferritin content, the transport of apical iron across the monolayer, and the influence of proinflammatory cytokines on these processes. Caco-2 cells accumulated transferrin-iron from the basolateral chamber by a temperature-dependent, saturable process that was enhanced in less differentiated cultures and attenuated by pre-exposure to high-iron medium. Exposure of Caco-2 cells to 10 μmol/L diferric transferrin for 36 hr increased cellular ferritin protein 3.4-fold and decreased the transport of apical 59Fe to the basolateral compartment by 45%. Pretreatment of cells with a combination of interleukin-1β, interleukin-6, and tumor necrosis factor-α increased transferrin-iron uptake by 70% and cellular ferritin content by 54%. Also, cytokine treatment decreased apical iron transport across the monolayer by 40% without altering paracellular transport of mannitol. These results suggest that transferrin-iron and proinflammatory cytokines are capable of modulating the iron status and iron transport activity of intestinal epithelial cells.

Intercellular adhesion molecule‐1 on cultured human epithelial cell lines: influence of proinflammatory cytokines

The expression of intercellular adhesion molecule-1 (CD54 or ICAM-1) on epithelial cells during acute or chronic inflammation may favor the interaction between epithelial cells and leukocytes expressing the natural ligands of ICAM-1, LFA-1 (CD11a/CD18), and Mac-1 (CD11b/CD18). We have evaluated in vitro the expression of ICAM-1 by a conjunctival (WK) and an intestinal (I407) human continuous epithelial cell line. Cells were cultured for 24 h in the presence or absence of IFN-gamma, TNF-alpha, IL-1 beta, IL-4, IL-6, IL-8, IL-10, and TGF-beta 1. Both epithelial cell lines showed a constitutive expression of ICAM-1. IFN-gamma at 500 U/ml and TNF-alpha at 200 ng/ml upregulated ICAM-1 expression; IL-1 beta at 100 pg/ml upregulated ICAM-1 on WK cells only. Cells cultured in the presence of both IFN-gamma and TNF-alpha exhibited a mean fluorescence intensity far greater than those cultured with IFN-gamma or TNF-alpha alone. I407 and WK cells were able to release soluble ICAM-1. IFN-gamma and TNF-alpha enhanced the release of sICAM-1. IL-4, IL-6, IL-8, IL-10, and TGF-beta 1 did not affect either ICAM-1 expression or sICAM-1 release. In conclusion, continuously cultured human epithelial cells may express ICAM-1 on their surface and release it in culture medium. These phenomena are upregulated by proinflammatory cytokines.

4 T-cell responses and cellular immunity in coeliac disease

Increasing evidence points to a direct role for T cells in the mediation of the coeliac intestinal lesion. There is good evidence for increased local T-cell reactivity, manifest as increased in T-cell activation in the lamina propria and T-cell proliferation in the epithelial compartment. A likely scenario is that gluten elicits antigen-specific responses by lamina propria T helper cells, probably of the Th1 (inflammatory-mediator) subtype, leading to secretion of pro-inflammatory cytokines. Such cytokines may have direct effects on intestinal enterocytes, as well as mediating indirect effects by upregulation of MHC antigens and by enhancing the activity of cytolytic T cells. Although gluten-specific IEL responses have not been demonstrated by intraepithelial T lymphocytes (IELs), increasing evidence suggests that IELs can act as cytolytic effector cells and hence are likely to exert enteropathic effects under the influence of pro-inflammatory cytokines.