scholarly journals Midkine in Inflammation

2011 ◽  
Vol 11 ◽  
pp. 2491-2505 ◽  
Author(s):  
Ludwig T. Weckbach ◽  
Takashi Muramatsu ◽  
Barbara Walzog
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Animal Models ◽  
Regulatory T Cells ◽  
Proinflammatory Cytokines ◽  
Inflammatory Diseases ◽  
Autoimmune Encephalitis ◽  
Heparin Binding ◽  
Inflammatory Processes

The 13 kDa heparin-binding growth factor midkine (MK) was originally identified as a molecule involved in the orchestration of embryonic development. Recent studies provided evidence for a new role of MK in acute and chronic inflammatory processes. Accordingly, several inflammatory diseases including nephritis, arthritis, atherosclerosis, colitis, and autoimmune encephalitis have been shown to be alleviated in the absence of MK in animal models. Reduced leukocyte recruitment to the sites of inflammation was found to be one important mechanism attenuating chronic inflammation when MK was absent. Furthermore, MK was found to modulate expression of proinflammatory cytokines and the expansion of regulatory T-cells. Here, we review the current understanding of the role of MK in different inflammatory disorders and summarize the knowledge of MK biology.

The role of cytokines in immunological tolerance: potential for therapy

2000 ◽  
Vol 2 (9) ◽  
pp. 1-20 ◽  
Author(s):  
Mark Harber ◽  
Anette Sundstedt ◽  
David Wraith
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
Animal Models ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Immunological Tolerance ◽  
Immunomodulatory Effects ◽  
Clinical Potential

Current immunosuppression protocols, although often effective, are nonspecific and therefore hazardous. Consequently, immunological tolerance that is antigen specific and does not globally depress the patient's immune system has become one of the Holy Grails of immunology. Since the discovery that cytokines have immunomodulatory effects, extensive research has investigated the potential of these molecules to induce and maintain specific immunological tolerance in the context of transplantation, allergy and autoimmunity. In this article, we review the possible mechanisms by which cytokines can modulate the immune response and the animal models that frequently confound the theory that a single cytokine, or group of cytokines, can induce tolerance in a predictable manner. Finally, we discuss the role of cytokines at a paracrine level, particularly in the context of inducing and maintaining antigen-specific, regulatory T cells with the clinical potential to suppress specific immune responses.

scholarly journals CD4+CD25+ Regulatory T Cells Can Mediate Suppressor Function in the Absence of Transforming Growth Factor β1 Production and Responsiveness

2002 ◽  
Vol 196 (2) ◽  
pp. 237-246 ◽  
Author(s):  
Ciriaco A. Piccirillo ◽  
John J. Letterio ◽  
Angela M. Thornton ◽  
Rebecca S. McHugh ◽  
Mizuko Mamura ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Regulatory T Cells ◽  
T Cell Activation ◽  
Transforming Growth Factor ◽  
Cell Contact ◽  
Suppressor Function ◽  
Tgf Β1

CD4+CD25+ regulatory T cells inhibit organ-specific autoimmune diseases induced by CD4+CD25−T cells and are potent suppressors of T cell activation in vitro. Their mechanism of suppression remains unknown, but most in vitro studies suggest that it is cell contact–dependent and cytokine independent. The role of TGF-β1 in CD4+CD25+ suppressor function remains unclear. While most studies have failed to reverse suppression with anti–transforming growth factor (TGF)-β1 in vitro, one recent study has reported that CD4+CD25+ T cells express cell surface TGF-β1 and that suppression can be completely abrogated by high concentrations of anti–TGF-β suggesting that cell-associated TGF-β1 was the primary effector of CD4+CD25+-mediated suppression. Here, we have reevaluated the role of TGF-β1 in CD4+CD25+-mediated suppression. Neutralization of TGF-β1 with either monoclonal antibody (mAb) or soluble TGF-βRII-Fc did not reverse in vitro suppression mediated by resting or activated CD4+CD25+ T cells. Responder T cells from Smad3−/− or dominant-negative TGF-β type RII transgenic (DNRIITg) mice, that are both unresponsive to TGF-β1–induced growth arrest, were as susceptible to CD4+CD25+-mediated suppression as T cells from wild-type mice. Furthermore, CD4+CD25+ T cells from neonatal TGF-β1−/− mice were as suppressive as CD4+CD25+ from TGF-β1+/+ mice. Collectively, these results demonstrate that CD4+CD25+ suppressor function can occur independently of TGF-β1.

scholarly journals The Role of iRhom2 in Metabolic and Cardiovascular-Related Disorders

2020 ◽  
Vol 7 ◽  
Author(s):  
Ramasatyaveni Geesala ◽  
Priya D. Issuree ◽  
Thorsten Maretzky
Keyword(s):  
Growth Factor ◽  
Inflammatory Diseases ◽  
Vascular Dysfunction ◽  
Growth Factor Receptor ◽  
Blood Cholesterol ◽  
Low Grade ◽  
Heparin Binding ◽  
Egfr Ligands ◽  
Inflammatory Stimuli

Chronic obesity is associated with metabolic imbalance leading to diabetes, dyslipidemia, and cardiovascular diseases (CVDs), in which inflammation is caused by exposure to inflammatory stimuli, such as accumulating sphingolipid ceramides or intracellular stress. This inflammatory response is likely to be prolonged by the effects of dietary and blood cholesterol, thereby leading to chronic low-grade inflammation and endothelial dysfunction. Elevated levels of pro-inflammatory cytokines such as tumor necrosis factor (TNF) are predictive of CVDs and have been widely studied for potential therapeutic strategies. The release of TNF is controlled by a disintegrin and metalloprotease (ADAM) 17 and both are positively associated with CVDs. ADAM17 also cleaves most of the ligands of the epidermal growth factor receptor (EGFR) which have been associated with hypertension, atherogenesis, vascular dysfunction, and cardiac remodeling. The inactive rhomboid protein 2 (iRhom2) regulates the ADAM17-dependent shedding of TNF in immune cells. In addition, iRhom2 also regulates the ADAM17-mediated cleavage of EGFR ligands such as amphiregulin and heparin-binding EGF-like growth factor. Targeting iRhom2 has recently become a possible alternative therapeutic strategy in chronic inflammatory diseases such as lupus nephritis and rheumatoid arthritis. However, what role this intriguing interacting partner of ADAM17 plays in the vasculature and how it functions in the pathologies of obesity and associated CVDs, are exciting questions that are only beginning to be elucidated. In this review, we discuss the role of iRhom2 in cardiovascular-related pathologies such as atherogenesis and obesity by providing an evaluation of known iRhom2-dependent cellular and inflammatory pathways.

scholarly journals Regulatory T cells in acute and chronic kidney diseases

2018 ◽  
Vol 314 (5) ◽  
pp. F679-F698 ◽  
Author(s):  
Rahul Sharma ◽  
Gilbert R. Kinsey
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Inflammatory Diseases ◽  
Kidney Diseases ◽  
Peripheral Tolerance ◽  
Autoimmune And Inflammatory Diseases

Foxp3-expressing CD4+ regulatory T cells (Tregs) make up one subset of the helper T cells (Th) and are one of the major mechanisms of peripheral tolerance. Tregs prevent abnormal activation of the immune system throughout the lifespan, thus protecting from autoimmune and inflammatory diseases. Recent studies have elucidated the role of Tregs beyond autoimmunity. Tregs play important functions in controlling not only innate and adaptive immune cell activation, but also regulate nonimmune cell function during insults and injury. Inflammation contributes to a multitude of acute and chronic diseases affecting the kidneys. This review examines the role of Tregs in pathogenesis of renal inflammatory diseases and explores the approaches for enhancing Tregs for prevention and therapy of renal inflammation.

scholarly journals Regulatory T Cells in the Control of Autoimmunity: the Essential Role of  Transforming Growth Factor β and Interleukin 4 in the Prevention of Autoimmune Thyroiditis in Rats by Peripheral CD4+CD45RC− Cells and CD4+CD8− Thymocytes

1999 ◽  
Vol 189 (2) ◽  
pp. 279-288 ◽  
Author(s):  
Benedict Seddon ◽  
Don Mason
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Regulatory T Cells ◽  
Autoimmune Thyroiditis ◽  
Transforming Growth Factor ◽  
Autoimmune Diabetes ◽  
Interleukin 4 ◽  
Protective Mechanism ◽  
Peripheral Cells

Previous studies have shown that induction of autoimmune diabetes by adult thymectomy and split dose irradiation of PVG.RT1u rats can be prevented by their reconstitution with peripheral CD4+CD45RC−TCR-α/β+RT6+ cells and CD4+CD8− thymocytes from normal syngeneic donors. These data provide evidence for the role of regulatory T cells in the prevention of a tissue-specific autoimmune disease but the mode of action of these cells has not been reported previously. In this study, autoimmune thyroiditis was induced in PVG.RT1c rats using a similar protocol of thymectomy and irradiation. Although a cell-mediated mechanism has been implicated in the pathogenesis of diabetes in PVG.RT1u rats, development of thyroiditis is independent of CD8+ T cells and is characterized by high titers of immunoglobulin (Ig)G1 antithyroglobulin antibodies, indicating a major humoral component in the pathogenesis of disease. As with autoimmune diabetes in PVG.RT1u rats, development of thyroiditis was prevented by the transfer of CD4+CD45RC− and CD4+CD8− thymocytes from normal donors but not by CD4+CD45RC+ peripheral T cells. We now show that transforming growth factor (TGF)-β and interleukin (IL)-4 both play essential roles in the mechanism of this protection since administration of monoclonal antibodies that block the biological activity of either of these cytokines abrogates the protective effect of the donor cells in the recipient rats. The prevention of both diabetes and thyroiditis by CD4+CD45RC− peripheral cells and CD4+CD8− thymocytes therefore does not support the view that the mechanism of regulation involves a switch from a T helper cell type 1 (Th1) to a Th2-like response, but rather relies upon a specific suppression of the autoimmune responses involving TGF-β and IL-4. The observation that the same two cytokines were implicated in the protective mechanism, whether thymocytes or peripheral cells were used to prevent autoimmunity, strongly suggests that the regulatory cells from both sources act in the same way and that the thymocytes are programmed in the periphery for their protective role. The implications of this result with respect to immunological homeostasis are discussed.

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