Synthesis Of Various Cytokines Research Articles

Interleukin 17 as a central component of the pathogenesis of pain associated with immunoinflammatory process: A new “target” of pharmacotherapy

Modern pathogenetic therapy of inflammatory rheumatic diseases (IRD) is aimed not only at reducing disease activity (although achieving remission and low disease activity remains the main goal of treatment), but also at eliminating as quickly and completely as possible the main symptoms that cause a decrease in the quality of life of patients. Particular importance is attached to effective control of chronic pain – the main and most distressing manifestation of IRD. To solve this problem, the pathogenesis of chronic pain in IRD continues to be actively studied, aimed at finding new ”targets” of pharmacotherapy. Thus, the role of central sensitization (CS) and comorbid fibromyalgia in the formation of clinical manifestations of IRD is now clearly proven. Signs of CS, depending on the instrument of its detection, are determined in 20–40% of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA).Interleukin (IL) 17 plays a fundamental role in the development of chronic pain in IIRD. This cytokine takes a leading position in the development of the ”cytokine cascade”, inducing the synthesis of various cytokines and chemokines, as well as chemotaxis and activation of neutrophils and T cells. Induction of synthesis of inflammatory mediators (including prostaglandin E2) determines the role of IL-17 in activation of nociceptors and their sensitization. IL-17 also takes an active part in neuroimmune interactions by activating glia cells and affecting receptors present on the membrane of neurons of the posterior horns of the spinal cord. This defines the role of IL-17 as one of the inductors of CS development. Pharmacologic blockade of IL-17 is a known pathway to suppress the activity of IIRPs such as PsA and AxSpA. However, this mechanism also allows for significant effects on chronic pain. In particular, the IL-17 inhibitor ixekizumab has shown high analgesic potential in a series of studies in PsA and AxSpA (SPIRIT-P1 and SPIRIT-P2, COAST V and COAST W). It is important to note that this drug demonstrated a very rapid analgesic effect: pain intensity was significantly reduced already 7 days after the first injection. These data suggest a specific effect of ixekizumab on the nociceptive system, independent of the anti-inflammatory effect. This fact allows us to consider ixekizumab as a drug of choice for the treatment of patients with PsA and AxSpA who experience severe pain and have signs of CS and fibromyalgia.

Severe Acute Respiratory Syndrome Coronavirus 2: The Role of the Main Components of the Innate Immune System.

At the end of December 2019, the COVID-19 pandemic began in Wuhan of China. COVID-19 affects different people with a wide spectrum of clinical manifestations, ranging from asymptomatic with recovery without hospitalization up to a severe acute respiratory syndrome (SARS). The innate and adaptive immunity appears responsible for the defense against the virus and recovery from the disease. The innate immune system, as the first line of defense, is essential for the detection of virus and subsequent activation of acquired immunity. The innate immune response is carried out by sentinel cells such as monocytes/macrophages and dendritic cells and by receptors known as pattern recognition receptors (PRR). These receptors can recognize various components of the virus, which lead to intracellular signaling and subsequently the synthesis of various cytokines. These cytokines then recruit other immune cells, activate adaptive immune responses, and inhibit viral spreading. The most common receptors include Toll-like receptors, C-type lectin receptors, and RIG-I like receptors. This review describes the current knowledge about the interplay between innate immune responses and SARS-CoV-2 with a focus on the innate immune cells and the role of their receptors in viral RNA recognition, as well as their mechanisms for recognizing SARS-CoV-2.

Inhibitory Effects of Tranilast on Cytokine, Chemokine, Adhesion Molecule, and Matrix Metalloproteinase Expression in Human Corneal Fibroblasts Exposed to Poly(I:C)

ABSTRACTPurpose/Aim: Viral infection of the cornea can result in inflammation and scarring and eventually cause blindness. Polyinosinic–polycytidylic acid [poly(I:C)], an analog of viral double-stranded RNA, induces the synthesis of various cytokines, chemokines, adhesion molecules, and matrix metalloproteinases (MMPs) in corneal fibroblasts. The effects of tranilast on the expression of these molecules in human corneal fibroblasts were examined.Materials and methods: Human corneal fibroblasts were cultured with or without poly(I:C) or tranilast. The release of the proinflammatory cytokine interleukin (IL)-6 and of the chemokines IL-8 and monocyte chemotactic protein-1 (MCP-1) was measured with enzyme-linked immunosorbent assays. The expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), MMP-1, and MMP-3 was evaluated by immunoblot or immunofluorescence analysis. The phosphorylation of mitogen-activated protein kinases (MAPKs), c-Jun (a component of the transcription factor AP-1), and IκB-α (an endogenous inhibitor of the transcription factor NF-κB) was examined by immunoblot analysis.Results: Tranilast inhibited in a concentration- and time-dependent manner the production of IL-6, IL-8, MCP-1, ICAM-1, VCAM-1, MMP-1, and MMP-3 by corneal fibroblasts exposed to poly(I:C). It also inhibited the poly(I:C)-induced phosphorylation of c-Jun and the MAPK JNK without affecting that of IκB-α or the MAPKs ERK and p38.Conclusions: Tranilast inhibited proinflammatory cytokine, chemokine, adhesion molecule, and MMP expression in human corneal fibroblasts exposed to poly(I:C), with these effects likely being mediated by attenuation of JNK-AP-1 signaling. Tranilast might therefore be expected to limit immune cell infiltration and stromal degradation associated with viral infection of the cornea.

Redefining the Systemic Inflammatory Response

From the first description of the "systemic inflammatory response" in the early 1990s, it has been recognized that this is a multifaceted response of the body to the combined insult of cardiothoracic surgery with bypass, involving causation by "activation of complement, coagulation, fibrinolytic, and kallikrein cascades, activation of neutrophils with degranulation and protease enzyme release, oxygen radical production, and the synthesis of various cytokines from mononuclear cells." Yet the intervening 15 years have seen a narrowing of research into individual systems and interventions naively targeted at single pathways without achieving clinically meaningful benefits. The time has come to redefine the systemic inflammatory response so that research can be more productively focused on objectively measuring and interdicting this multisystem disorder. A key concept of this new understanding is that translation into a hard adverse event occurs when the systemic imbalance is combined with a localized trigger. Triggers might be inadvertently provided by transient episodes of ischemia/malperfusion to vulnerable organs or handling trauma to major vessels. Future research should be directed at suppressing systemic activation with combinations of drugs and improved circuit coating, whereas changes in clinical practice and continuous monitoring of perfusion parameters can help eliminate localized triggering events.

Fibronectin Stimulates Endothelin-1 Synthesis in Rat Hepatic Myofibroblasts via a Src/ERK-Regulated Signaling Pathway

Liver injury serves as an excellent model of wound healing, characterized by increased synthesis of various cytokines and peptides, including the vasoactive peptide endothelin-1. In the liver, wound healing is mediated by effector cells such as hepatic stellate cells, which cause tissue contraction. Endothelin-1 has autocrine effects on stellate cells and induces their contractile activities. We explored the role of various extracellular matrix components, particularly of fibronectin, in regulating endothelin-1 production during liver injury. Hepatic stellate cells were isolated from normal and injured rats. Real-time polymerase chain reaction immunoblot and enzyme-linked immunosorbent assay analyses were used to measure specific variables, including endothelin-1 production. Preproendothelin-1 promoter activity was determined by a luciferase assay. Stellate cell contraction was measured by a gel contraction assay. Fibronectin stimulated transcription of preproendothelin-1 messenger RNA and expression of endothelin through an integrin-dependent pathway in activated hepatic stellate cells. In these cells, fibronectin induced phosphorylation/activation of extracellular signal-regulated kinase (ERK) through a Shc- and Src-dependent mechanism; ERK activation was required for fibronectin-induced endothelin-1 expression. Fibronectin stimulation by stellate cells induced expression of smooth muscle alpha-actin and endothelin-1-mediated autocrine stellate cell contraction. Stellate cells isolated from injured livers of rats exhibited increased basal phosphorylation levels of Src, Shc, and ERK, as well as increased endothelin-1 synthesis. Fibronectin stimulates activated stellate cells to produce endothelin-1 and contract, via an ERK-dependent signaling pathway. The resulting autocrine functional effects of endothelin-1 are likely to be important in the wound-healing process in injured liver.

Physiology of adaptive immunity regulation via signaling pattern-recognition receptors

In the past fifty years, adaptive immune response has been studied from the standpoint of Burnet’s clonal selection theory. Much progress in understanding the mechanisms of specific cellular (T-cell) and antibody (B-cell) immune response has been made. However, it remained unclear why different pathogen types induce principally different types of immune response. Effective immune response in different cases may develop either by cellular or humoral type, and antibodies are produced on the basis of immunoglobulins of different classes. These facts could only be explained by specific regulation of differentiation of immunocompetent cells during the development of adaptive immune response to different pathogens. The discovery of the system of signaling pattern-recognition receptors (PRRs) in immunocompetent cells made it possible to understand these specific physiological mechanisms of regulation of T- and B-cell response to various pathogens. Upon interaction with pathogens, signaling PRRs activate the synthesis of various cytokines in the cells, which then regulate further activation of cells in different directions. Dendritic cells not only provide naive T cells with a processed antigen but also supply them with various cytokines inducing formation of type 1 or 2 T-helpers; as a result, adaptive immune response develops by the cellular or humoral type, respectively. Antigens of pathogens activate PRRs in B lymphocytes, which initiate the synthesis of various cytokines in cells. These are cytokines that determine predominant production by plasma cells of class A, M, G, or E antibodies depending on the pathogen type.

Consensus Statement: Defining Minimal Criteria for Reporting the Systemic Inflammatory Response to Cardiopulmonary Bypass

The causal factors of the systemic inflammatory response to cardiopulmonary bypass (CPB) were correctly identified in the early 1990 s: "... activation of complement, coagulation, fibrinolytic, and kallikrein cascades, activation of neutrophils with degranulation and protease enzyme release, oxygen radical production, and the synthesis of various cytokines from mononuclear cells" [Butler 1993]. Why therefore have clinical advances to curb the systemic inflammatory response proven such a disappointment? Part of the problem is that cardiac surgery has never taken intellectual ownership of this issue, borrowing its diagnosis from critical care medicine and failing to define the minimal criteria that should be measured when reporting on the systemic inflammatory response. An evidence based review of the current literature by many of the coauthors on this paper found that the majority of studies on the systemic inflammatory response did not measure a single one of the causal factors listed above - thus hindering our ability to identify mechanisms of causation and identify drug targets [Landis 2008]. A panel of experts convened at the Outcomes XII meeting, Barbados 2008, drafted the present consensus document in order to provide a framework to guide future studies and interdictions of the systemic inflammatory response. Herein, we have recommended: 1) mandatory reporting of minimal CPB and perfusion criteria that may affect outcomes, 2) reporting of a minimal set of causal inflammatory markers linked to adverse sequelae, and 3) reporting of at least one clinical end-point of organ injury, from a list of endpoints and markers of organ injury that balance practicality with clinical meaningfulness. It is our collective belief that this document will serve as a foundation for furthering our understanding of the influence of CPB practice with the systemic inflammatory response by standardizing the reporting of research findings in the peer-reviewed literature.

Temporal Differences in the Ability of Ethanol to Modulate Endotoxin‐Induced Increases in Inflammatory Cytokines in Muscle Under In Vivo Conditions

Acute alcohol (EtOH) intoxication may both antagonize and potentiate the ability of monocytes/macrophages to respond to endotoxin (lipopolysaccharide [LPS]). The suppressive effects of EtOH predominate when the duration between EtOH and LPS administration is relatively short, whereas sensitization is observed under conditions when there is a relatively longer delay between EtOH and LPS exposure. Striated muscle is now recognized to possess components of both the afferent and efferent limbs of the innate immune system. The aim of the present study was to determine whether the interval between EtOH and LPS administration differentially affects the mRNA content for selected elements of the innate immune response in skeletal and cardiac muscle and to compare such changes with those occurring in liver and spleen. The content of mRNA for interleukin (IL)-6, IL-1beta, tumor necrosis factor (TNF)-alpha, and high-mobility group box (HMGB)-1, as well as toll-like receptors (TLRs)-2 and -4, were measured in gastrocnemius, heart, liver and spleen from rats orally gavaged with EtOH and then injected with LPS either two or 24 hr thereafter. EtOH intoxication two hr before LPS acutely suppressed the increased IL-6 mRNA in all tissues and antagonized the increase in plasma and tissue IL-6 protein concentration. Similarly, EtOH blunted the LPS-induced increase in tissue mRNA expression of TNF-alpha and IL-1beta. In contrast, when LPS was given 24 hr after EtOH, the increased IL-6 in striated muscle, but not in liver or spleen, was selectively potentiated. An enhanced LPS responsiveness was also observed for the late-phase cytokine HMGB1 in all tissues; however, the increased tissue expression of TNF-alpha and IL-1beta induced by LPS was not augmented. TLR4 mRNA was decreased in both heart and spleen (but unaltered in skeletal muscle and liver) of rats injected with LPS, and this change was prevented by pretreatment with EtOH. In contrast, EtOH alone increased TLR-2 mRNA content of heart, liver, and spleen but not muscle. LPS also markedly increased TLR2 mRNA in the same three tissues under control conditions, but this increase was attenuated by EtOH administered either two or 24 hr before LPS. Under in vivo conditions, the interval between EtOH exposure and LPS differentially affected the synthesis of various cytokines. In this regard, EtOH administered within two hr of LPS generally suppressed IL-6, IL-1beta, and TNF-alpha mRNAs in muscle, heart, liver, and spleen. Delaying the exposure of animals to LPS for 24 hr after EtOH, however, accentuated the increase in IL-6 and HMGB1, and for IL-6, this increased sensitivity appeared localized to striated muscle.

Safflower polysaccharides activate the transcription factor NF-κB via Toll-like receptor 4 and induce cytokine production by macrophages

Two active polysaccharide fractions (SF1 and SF2) purified from dried safflower petals ( Carthamus tinctorius L.) stimulated the synthesis of various cytokines by peritoneal macrophages. In a number of cell types, SF1 and SF2 induced a rapid degradation of IκBα essential for the activation of the transcription factor NF-κB. Toll-like receptor 4 (TLR4), but not TLR2, was expressed in all cell lines that responded to SF1 and SF2. Enforced expression of TLR4 and MD-2 rendered responsiveness to SF1 and SF2. Moreover, these safflower polysaccharides failed to induce the production of TNF-α and NO by peritoneal macrophages prepared from C3H/HeJ mice that have a point mutation in the Tlr4 gene. Thus, these observations clearly indicate that safflower polysaccharides activate the NF-κB signaling pathway via TLR4.

SENDAI VIRUS INDUCES VARIOUS CYTOKINES IN HUMAN PERIPHERAL BLOOD LEUKOCYTES: DIFFERENT SUSCEPTIBILITY OF CYTOKINE MOLECULES TO LOW pH

Virus infection of cell cultures induces the synthesis of various cytokines which can either inhibit or stimulate virus replication. The Sendai virus induces large quantities of biologically active interferon (IFN-αn3) in human peripheral blood leukocytes (hPBL) in vitro, as well as many other cytokines. The supernatants of Sendai virus-infected hPBL contained biologically active IFN-αn3, significant amounts of immunogenic IFN-γ, monokines (IL-1α, IL-β, TNF-α), lymphokines (IL-6, TNF-β), growth factor (PDGF-AB) and small concentrations of IL-2 and GM-CSF. The analysis of the influence of the Sendai virus inactivation by lowering pH 2.0 on the cytokine concentrations showed that IL-1α, TNF-α, TNF-β and IFN-γ are susceptible to acid conditions, while IFN-αn3, IL-1β, IL-6 and IL-2 concentrations remained unchanged.

Involvement of β1 and β2 Integrin Stimulation in RNA Synthesis in an Eosinophilic Cell Line (EoL-1)

In allergic inflammatory disease, especially in bronchial asthma, eosinophils play important roles as essential inflammatory cells. In the accumulation of eosinophils in airway inflammation, eosinophils receive very diverse stimuli. In this study, we investigated the influences of the signal between β₂ integrin/intercellular adhesion molecule-1 (ICAM-1) or β₁ integrin/fibronectin (FN) and RNA synthesis on proteins in eosinophilic cell line-1 (EoL-1), using recombinant soluble ICAM-1 (r-sICAM-1) as a global response of eosinophils. ³H-thymidine incorporation and ³H-uridine incorporation were used as indices for DNA synthesis and RNA synthesis, respectively. In a comparison of the RNA/DNA ratio with various durations of stimulation of 1 µg/ml of r-sICAM-1 and 100 µg/ml of FN, a time-dependent increase was observed, but the increase induced by FN rose slower than that induced by r-sICAM-1. From this result, a β₂ integrin/ICAM-1 signal induced an increase in the RNA/DNA ratio in EoL-1, implying that the signal promotes RNA synthesis, which suggests that various types of protein synthesis, such as the synthesis of various cytokines, are induced by the β₂ integrin/ICAM-1 signal. Similar results were obtained with a β₁ integrin signal using FN, but there was a difference in the time course between β₂ integrin/ICAM-1 and β₁ integrin/FN signals. This experimental method may be useful for understanding these manifestations as a global response of eosinophils.

IL-13 inhibits TNF production but potentiates that of IL-6 in vivo and ex vivo in mice.

IL-13 was reported to inhibit the synthesis of various cytokines in vitro, including that of TNF. It has divergent effects on IL-6 production, which is increased in endothelial cells and decreased in monocytes. We studied the effect of IL-13 administration on TNF and IL-6 production in vivo in mice. IL-13 (1 microg/mouse, i.v., 10 min to 6 h before LPS) decreased LPS (100 ng/mouse, i.v.)-induced serum TNF levels by 50%, while it increased the levels of IL-6 by fourfold. IL-13 potentiated IL-1beta (100 ng/mouse, i.v.)-induced serum IL-6 levels as well as IL-1- or LPS-induced serum amyloid A. When blood from IL-13-treated mice was stimulated with LPS in vitro, TNF production was decreased fivefold, and that of IL-6 was slightly decreased. We also cultured in vitro the aorta obtained from IL-13-pretreated mice and found that they produce more IL-6 (up to sevenfold) than aorta from control mice. Little or no TNF could be detected in these samples. Thus, IL-13 in vivo inhibits serum TNF but up-regulates serum IL-6. The differential regulation of IL-6 and TNF together with the results of ex vivo experiments could be explained by hypothesizing that the cellular origins of the two cytokines are different.

The Role of Cytokines in Gestation

Lymphohemopoietic cytokines are now recognized to be central participants in the cellular communication events underlying the complex and dynamic remodeling processes required to accommodate the semiallogeneic conceptus during mammalian reproduction. Cytokines are identified to be particular importance in mediating communications between the conceptus and maternal cells, particularly the uterine epithelium and infiltrating leukocytes, both prior to implantation and as the placenta develops. In this review we summarize recent experimental data concerning the synthesis of various cytokines in uterine and conceptus-derived tissues and highlight current hypotheses for their roles in establishing and maintaining successful pregnancy. It is concluded that complex and finely balanced cytokine networks underpin precise regulatory mechanisms controlling the rate and degree of conceptus development and invasion into maternal tissues.

Disulfide bond assignments and secondary structure analysis of human and murine interleukin 10.

Interleukin 10 (IL-10), which was first discovered by its ability to inhibit the synthesis of various cytokines, most notably gamma interferon, from Th1 helper cells, displays pleiotropic immunoregulatory properties. Human and murine IL-10 have a high amino acid sequence identity (ca. 73%) which includes the conservation of all four cysteine residues in human IL-10 and the first four out of five cysteine residues for murine IL-10. Chemical analysis was used to determine that both recombinant human and recombinant murine IL-10 contain two disulfide bonds. The disulfide pairs for each were determined by mass spectrometric and reversed-phase HPLC analysis of trypsin-derived polypeptide fragments. The disulfide bond assignments for both species were similar in that the first cysteine residue in the sequence paired with the third and the second paired with the fourth. The fifth cysteine in murine IL-10 was determined by chemical modification to be unpaired. Far-UV circular dichroism analysis indicated that the secondary structure of recombinant human and murine IL-10 are composed of ca. 60% alpha-helix. Reduction of the disulfide bonds structurally destabilized the protein and led to a structure containing only 53% alpha-helix. The reduced protein displayed no in vitro biological activity in a mast cell proliferation assay. These studies indicate that IL-10 is a highly alpha-helical protein containing two disulfide bonds, either one or both of which are critical for its structure and function. In addition, these properties suggest that this interesting cytokine may belong to the alpha helical cytokine class of hematopoietic ligands.