Course Of Inflammatory Responses Research Articles

Tissue-specific control of galectin-1-driven circuits during inflammatory responses.

The relevance of glycan-binding proteins in immune tolerance and inflammation has been well established, mainly by studies of C-type lectins, siglecs and galectins, both in experimental models and patient samples. Galectins, a family of evolutionarily conserved lectins, are characterized by sequence homology in the carbohydrate-recognition domain, atypical secretion via an endoplasmic reticulum-Golgi-independent pathway and by the ability to recognize β-galactoside-containing saccharides. Galectin-1 (Gal-1), a prototype member of this family, displays mainly anti-inflammatory and immunosuppressive activities, although, similar to many cytokines and growth factors, it may also trigger paradoxical pro-inflammatory effects under certain circumstances. These dual effects could be associated to tissue-, time- or context-dependent regulation of galectin expression and function, including particular pathophysiologic settings and/or environmental conditions influencing the structure of this lectin, as well as the availability of glycosylated ligands in immune cells during the course of inflammatory responses. Here, we discuss the tissue-specific role of Gal-1 as a master regulator of inflammatory responses across different pathophysiologic settings, highlighting its potential role as a therapeutic target. Further studies designed at analyzing the intrinsic and extrinsic pathways that control Gal-1 expression and function in different tissue microenvironments may contribute to delineate tailored therapeutic strategies aimed at positively or negatively modulating this glycan-binding protein in pathologic inflammatory conditions.

Immune Responses and Anti-inflammatory Strategies in a Clinically Relevant Model of Thromboembolic Ischemic Stroke with Reperfusion.

The poor clinical relevance of experimental models of stroke contributes to the translational failure between preclinical and clinical studies testing anti-inflammatory molecules for ischemic stroke. Here, we (i) describe the time course of inflammatory responses triggered by a thromboembolic model of ischemic stroke and (ii) we examine the efficacy of two clinically tested anti-inflammatory drugs: Minocycline or anti-CD49d antibodies (tested in stroke patients as Natalizumab) administered early (1h) or late (48h) after stroke onset. Radiological (lesion volume) and neurological (grip test) outcomes were evaluated at 24h and 5days after stroke. Immune cell responses peaked 48h after stroke onset. Myeloid cells (microglia/macrophages, dendritic cells, and neutrophils) were already increased 24h after stroke onset, peaked at 48h, and remained increased-although to a lesser extent-5days after stroke onset. CD8+ and CD4+ T-lymphocytes infiltrated the ipsilateral hemisphere later on (only from 48h). These responses occurred together with a progressive blood-brain barrier leakage at the lesion site, starting 24h after stroke onset. Lesion volume was maximal 24-48h after stroke onset. Minocycline reduced both lesion volume and neurological deficit only when administered early after stroke onset. The blockade of leukocyte infiltration by anti-CD49d had no impact on lesion volume or long-term neurological deficit, independently of the timing of treatment. Our data are in accordance with the results of previous clinical reports on the use of Minocycline and Natalizumab on ischemic stroke. We thus propose the use of this clinically relevant model of thromboembolic stroke with recanalization for future testing of anti-inflammatory strategies for stroke.

Potential therapeutic use of IL-37: a key suppressor of innate immunity and allergic immune responses mediated by mast cells.

The host response to either exogenous or endogenous insults produces a series of changes, characterized by alterations in immunological functions and generation of mediators called cytokines which include the interleukin-1 (IL-1) family members. IL-1 acts as a hormone mediating the host responses to infection and inflammation. Blocking inflammatory IL-1 family members can be effective against inflammatory disorders, including allergies. IL-37, (formerly IL-1 family member 7), emerges as an inhibitor of innate and adaptive immunity by reducing circulating and organ cytokine levels. IL-37, mainly expressed in dendritic cells, monocytes, and plasma cells after TIR ligand activation, inhibits inflammatory cytokines and augments the level of anti-inflammatory IL-10. IL-37 is involved in allergic reaction and its expression in dendritic cells causes tollerogenicity and inhibits inflammatory response. Mast cells (MCs) are ubiquitous in the body, reside in numerous mucosal tissues, and are mediators of allergic reaction, and innate and adaptive immunity. MCs are important regulators of cytokine generation in the course of inflammatory responses and allergy, and are implicated in the pathophysiology of allergic asthma. Cysteine protease caspase-1 activation leads to the cleavage of pro-form of IL-1 into active mature IL-1 which is present in stimulated and unstimulated inflammatory MCs. Inflammatory cytokine inhibition, along with the augmentation of anti-inflammatory IL-10 by IL-37, is certainly beneficial and improves the pathogenesis of allergic disorders. However, in these studies, the exact mechanism(s) of IL-37-induced anti-inflammatory and anti-allergic activity along with its side effect(s) remain to be determined.

Human Primary Keratinocytes Show Restricted Ability to Up-regulate Suppressor of Cytokine Signaling (SOCS)3 Protein Compared with Autologous Macrophages

Suppressor of cytokine signaling (SOCS)3 belongs to a family of proteins that are known to exert important functions as inducible feedback inhibitors and are crucial for the balance of immune responses. There is evidence for a deregulated immune response in chronic inflammatory skin diseases. Thus, it was the aim of this study to investigate the regulation of SOCS proteins involved in intracellular signaling pathways occurring during inflammatory skin diseases and analyze their impact on the course of inflammatory responses. Because we and others have previously described that the cytokine IL-27 has an important impact on the chronic manifestation of inflammatory skin diseases, we focused here on the signaling induced by IL-27 in human primary keratinocytes compared with autologous blood-derived macrophages. Here, we demonstrate that SOCS3 is critically involved in regulating the cell-specific response to IL-27. SOCS3 was found to be significantly up-regulated by IL-27 in macrophages but not in keratinocytes. Other STAT3-activating cytokines investigated, including IL-6, IL-22, and oncostatin M, also failed to up-regulate SOCS3 in keratinocytes. Lack of SOCS3 up-regulation in skin epithelial cells was accompanied by prolonged STAT1 and STAT3 phosphorylation and enhanced CXCL10 production upon IL-27 stimulation compared with macrophages. Overexpression of SOCS3 in keratinocytes significantly diminished this enhanced CXCL10 production in response to IL-27. We conclude from our data that keratinocytes have a cell type-specific impaired capacity to up-regulate SOCS3 which may crucially determine the course of chronic inflammatory skin diseases.

Cytokines in cutaneous lupus erythematosus

Clinical manifestations of cutaneous lupus erythematosus are diverse and different subtypes of the disease have been defined. It is characteristic for lupus skin inflammation that a significant activation of innate interferon pathways is observable. Endogenous molecules indicative for tissue damage (damage-associated molecular patterns [DAMPs]) show cytokine-like properties once released from intracellular compartments and these DAMPs have been shown to influence the course of inflammatory responses. Cytokines including TNF-α and IL-1 family members significantly contribute to the chronic inflammatory phenotype and, in combination with DAMPs, impact on the activation of innate interferons. A better understanding of the deregulated cytokine network in cutaneous lupus erythematosus patients with distinct disease phenotypes and genetic backgrounds is of high importance and a prerequisite for recommending and developing more individualized therapeutic strategies.

Collagenase-2 (MMP-8) as a point-of-care biomarker in periodontitis and cardiovascular diseases. Therapeutic response to non-antimicrobial properties of tetracyclines

Neutrophil collagenase or collagenase-2 (matrix metalloproteinase [MMP]-8) belongs to the collagenase subgroup of the MMP superfamily of calcium- and zinc-dependent neutral proteinases. MMP-8 is catalytically the most competent proteinase to initiate type I collagen and extracellular matrix degradation associated with periodontal and peri-implant tissue destruction leading to tooth and dental implant loss. Regarding cardiovascular diseases, pathologically excessive MMP-8 has been implicated in atherosclerotic plaque destabilization and rupture probably through its proteolytic ability to thin the protecting collagenous fibrous cap lining coronary and other arteries. During the initiation and course of inflammatory responses in periodontitis, peri-implantitis and cardiovascular diseases, proinflammatory mediators including especially MMP-8 are up-regulated not only in affected tissues but also in the secreted, disease-affected, oral fluids (gingival crevicular fluid [GCF], peri-implant sulcular fluid [PISF], mouthrinse and saliva) as well as in serum and plasma. Regarding periodontitis, peri-implantitis and cardiovascular diseases, the oral fluid and serum MMP-8 analysis has proven to be a sensitive and an objective biomarker as an indicator of health, pathologic processes and pharmacologic response to therapeutic intervention including doxycycline medication as an MMP inhibitor. Oral fluids, i.e., GCF, PISF, mouthrinse and saliva are easily and non-invasively collected for the site- and patient-specific diagnostic analysis in periodontitis and peri-implantitis, whereas serum and/or plasma sample collection is required for diagnosis and monitoring of cardiovascular diseases. Research in periodontology and cardiology has identified a need for the development of innovative point-of-care diagnostic tests for MMP-8. We summarize and review the recent studies on these topics.

Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution

Lipoxins (LXs) or the lipoxygenase interaction products are generated from arachidonic acid via sequential actions of lipoxygenases and subsequent reactions to give specific trihydroxytetraene-containing eicosanoids. These unique structures are formed during cell–cell interactions and appear to act at both temporal and spatially distinct sites from other eicosanoids produced during the course of inflammatory responses and to stimulate natural resolution. Lipoxin A 4 (LXA 4) and lipoxin B 4 (LXB 4) are positional isomers that each possesses potent cellular and in vivo actions. These LX structures are conserved across species. The results of numerous studies reviewed in this work now confirm that they are the first recognized eicosanoid chemical mediators that display both potent anti-inflammatory and pro-resolving actions in vivo in disease models that include rabbit, rat, and mouse systems. LXs act at specific GPCRs as agonists to regulate cellular responses of interest in inflammation and resolution. Aspirin has a direct impact in the LX circuit by triggering the biosynthesis of endogenous epimers of LX, termed the aspirin-triggered 15-epi-LX, that share the potent anti-inflammatory actions of LX. Stable analogs of LXA 4, LXB 4, and aspirin-triggered lipoxin were prepared, and several of these display potent actions in vitro and in vivo. The results reviewed herein implicate a role of LX and their analogs in many common human diseases including airway inflammation, asthma, arthritis, cardiovascular disorders, gastrointestinal disease, periodontal disease, kidney diseases and graft-vs.-host disease, as well as others where uncontrolled inflammation plays a key role in disease pathogenesis. Hence, the LX pathways and mechanisms reviewed to date in this work provide a basis for new approaches to treatment of many common human diseases that involve inflammation.

IL-12 or IL-4 Prime Human NK Cells to Mediate Functionally Divergent Interactions with Dendritic Cells or Tumors

In the course of inflammatory responses in peripheral tissues, NK cells may be exposed to cytokines such as IL-12 and IL-4 released by other cell types that may influence their functional activities. In the present study we comparatively analyzed purified human peripheral blood NK cells that had been exposed to either IL-12 or IL-4 during short (overnight) incubation. We show that although IL-12-cultured NK cells produced abundant IFN-gamma, TNF-alpha, and GM-CSF in response to stimuli acting on the NKp46-activating receptor, IL-4-cultured NK cells did not release detectable levels of these cytokines. In contrast, IL-4-cultured NK cells produced significant levels of TNF-alpha and GM-CSF only when stimulated with PMA and ionomycin. In no instance could the production of IL-5 and IL-13 be detected. Importantly, IL-12-cultured, but not IL-4-cultured, NK cells displayed strong cytolytic activity against various tumor cells or immature dendritic cells (DCs). Moreover, only NK cells that had been cultured in IL-12 were able to induce substantial DC maturation. Our data suggest that NK cells exposed to IL-12 for a time interval compatible with in vivo responses may favor the selection of appropriate mature DCs for subsequent Th1 cell priming in secondary lymphoid organs. On the contrary, NK cells exposed to IL-4 do not exert DC selection, may impair efficient Th1 priming, and favor either tolerogenic or Th2-type responses.

Developmental Phases of Inflammation-Induced Massive Lymphoid Hyperplasia and Extensive Changes in Epithelium in an Experimental Model of Allergy

Direct evidence that inflammation is linked to carcinogenesis has yet to be established. Very few data are available on the developmental phases of inflammation-induced immune dysfunction that may lead to tumorigenesis. In a series of studies conducted in the 1980s and 1990s, an experimental model of acute and chronic inflammation was established in guinea pig conjunctiva by topical application of fluoresceinyl ovalbumin (FLOA) for up to 30 months. In this updated report, some of the findings are reanalyzed and expanded to identify that at lease 3 developmental phases were involved during the entire course of inflammatory responses including (1) an acute response (phase A) involving IgE-mast cell sensitization and degranulation; (2) an intermediate phase (phase B), a desensitization phenomenon and loss of mast cell function and neovascularization; (3) a chronic response (phase C) and induction of massive lymphoid hyperplasia, follicular formation with germinal centers, increased swollen goblet cells, extensive epithelial thickening and thinning, and angiogenesis. The results suggest evidence of a direct association between inflammation and the development of tumor-like lesions in lymphoid tissues and extensive changes in adjacent epithelia. Confirmation that inflammation induces irreversible changes in lymphoid and epithelial tissues leading to lymphoid tumorigenesis and/or carcinogenesis requires further studies. Understanding the developmental phases of immune dysfunction may provide unique opportunities for diagnosis and treatment of inflammatory diseases, autoimmune disorders, and cancers including lymphomas associated with Sjogren syndrome, squamous cell carcinoma of the conjunctiva, and other lymphomas or epithelial cancers. It is suggested that inflammatory mediators are ideal targets (biomarkers) for diagnosis, chemoprevention, and therapy for several cancers.

Interactions between leukocytes and endothelial cells in gout: lessons from a self-limiting inflammatory response

Chapter summaryInteractions with endothelium are necessary for leukocytes to pass from the blood into extravascular tissues, and such interactions are facilitated in inflammation by the coordinated expression of endothelial adhesion molecules and chemoattractants. Although the general mechanisms and intracellular pathways of endothelial activation are now fairly well characterised in vitro, relatively little detailed information exists on how endothelial activation changes during the course of inflammatory responses and how such change influences the amount of leukocyte recruitment and the types of leukocytes recruited. Having developed a radiolabelled-antibody-uptake technique for quantifying the expression of endothelial adhesion molecules in relation to leukocyte trafficking, we have analysed the acute, self-limiting inflammatory response to injection of monosodium urate (MSU) crystals. Our studies have supported the view that endothelial activation is closely paralleled by leukocyte recruitment at the onset of the response and have highlighted separate vascular and extravascular stages of downregulation. More recent studies addressing the extravascular contribution to downregulation point to an important role for monocyte–macrophage differentiation in limiting further endothelial activation as a consequence of phagocytosis of MSU crystals.

Suppression of endothelin-converting enzyme-1 by sucralfate, a factor in gastric mucosal resistance to indomethacin injury in rats

Aims: Endothelin-1 (ET-1), a key mediator of inflammatory processes associated with gastric mucosal injury, is a potent vasoactive peptide produced from a biologically inactive big ET-1 by the action of endothelin-converting enzyme-1 (ECE-1). In this study, we investigated gastric mucosal expression of ECE-1 during a 16 h course of inflammatory responses associated with gastric mucosal damage caused by indomethacin, and evaluated the effect of pretreatment with an antiulcer agent, sucralfate, on this process. ___TAGSTART___BR___TAGEND___Methods: The experiments were conducted with groups of rats pretreated intragastrically with sucralfate at 200 mg/kg or vehicle, followed 30 min later by an intragastric dose of indomethacin at 60 mg/kg, and at different time (2, 4, 8, and 16 h) intervals, their stomachs were used for macroscopic and biochemical assessments. ___TAGSTART___BR___TAGEND___Results: Examination of gastric mucosa from the control animals revealed that, within 2 h, indomethacin caused multiple hemorrhaging lesions, the extent of which reached a maximum after 4 h and was accompanied by a 4-fold enhancement in the expression of ECE-1 activity, and a marked elevation in ET-1 (4.5-fold), TNF-α (11.3-fold) and apoptosis (29.9-fold). Pretreatment with sucralfate produced within 2 h a 59.7% reduction in the extent of mucosal damage caused by indomethacin, while an 81% reduction in lesion was observed after 16 h. This effect of sucralfate was accompanied by a significant reduction in the mucosal expression of ECE-1, the activity of which declined by 57.3% within 2 h following sucralfate, while a 38.4% decline in the indomethacin-induced expression of ECE-1 was attained after 16 h. Moreover, the reduction in the severity of damage following pretreatment with sucralfate was reflected at the end of 16-h period in a 47.4% decrease in the mucosal expression of TNF-α, 25.1% decline in ET-1, and a 38.9% decline in apoptosis. ___TAGSTART___BR___TAGEND___Conclusions: The results demonstrate that gastric mucosal injury by indomethacin is associated with up-regulation of ECE-1 expression, which leads to the enhancement of ET-1 production, induction of TNF-α, and triggering of apoptotic events that exacerbate the inflammatory process. Our findings also show that sucralfate protection against gastric mucosal injury caused by indomethacin involves the suppression of the mucosal ECE-1 activity.

Induction of Endothelin-Converting Enzyme-1 in Gastric Mucosal Injury by Idomethacin

Endothelin-1 (ET-1) is a 21-amino acid vasoactive peptide produced from a 39-amino acid biologically inactive peptide, big ET-1, by the action of endothelin-converting enzyme-1 (ECE-1). We investigated gastric mucosal expression of ECE-1 during a 16 h course of inflammatory responses associated with gastric mucosal injury caused by indomethacin. The extent of gastric mucosal damage reached a maximum 4 h following the drug, and was accompanied by a 3.9-fold enhancement in the expression of ECE-1 activity and a significant elevation in ET-1 (4.5-fold), TNF-α (11.3-fold), and apoptosis (29.9-fold). A 37.2% decrease in the severity of lesion 16 h following the drug was associated with a 44.5% reduction in the mucosal expression of ECE-1 activity and a decline in TNF-α (64%), ET-1 (65.2%), and apoptosis (72.3%). The results demonstrate that gastric mucosal injury by indomethacin is associated with up-regulation of ECE-1 expression, which leads to the enhancement of ET-1 production, induction of TNF-α, and triggering apoptotic events that disrupt gastric mucosal homeostasis.

Up-Regulation of Endothelin-Converting Enzyme-1 in Gastric Mucosal Inflammatory Responses to Helicobacter pylori Lipopolysaccharide

Endothelin-1 (ET-1) is a vasoactive peptide produced from a biologically inactive big ET-1 by the action of endothelin-converting enzyme-1 (ECE-1). We investigated gastric mucosal expression of ECE-1 during a 10-day course of inflammatory responses associated with acute gastritis elicited by Helicobacter pylori lipopolysaccharide. The ECE-1 activity was associated with microsomal fraction and the level of its expression reflected the extent of mucosal inflammatory involvement. The histologic pattern of inflammation reached a maximum on the 4th day following the lipopolysaccharide and was accompanied by a 4.1-fold enhancement in the expression of ECE-1 activity and a significant elevation in ET-1 (3.1-fold), TNF-α (8.8-fold), and apoptosis (11.6-fold). A 41.5% decrease in the severity of mucosal inflammation by the 10th day following the lipopolysaccharide was reflected in a 62.3% reduction in the mucosal expression of ECE-1 and a decline in TNF-α, ET-1, and apoptosis. Thus, H. pylori infection causes up-regulation of gastric mucosal ECE-1 expression, which leads to the enhancement of ET-1 production, induction of TNF-α, and triggering the apoptotic events that exacerbate the inflammatory process.

歯肉線維芽細胞のヒアルロン酸合成酵素発現に及ぼすアデノシンの影響

Adenosine, an endogenous nucleoside, has a plethora of biological actions on a large variety of cells and can modulate the various functions of cells involved in inflammatory responses. On the other hand, production of extracellular matrices is one of the critical functions of fibroblasts. Among various extracellular matrices, hyaluronate (HA) plays important roles in migration, growth and differentiation of a variety of cells during the course of inflammatory reactions and process of wound healing.In this study, we investigated the expression of adenosine receptor subtypes in human gingival fibroblasts (HGF) and examined the effects of adenosine on the HA production of HGF by utilizing various agonists specific for adenosine receptor subtypes.Concerning the expression of adenosine receptors, RT-PCR analysis revealed that HGF expressed adenosine receptor A1, A2 a, and A2 b, but not A3 mRNA. Ligation of adenosine receptors by adenosine or adenosine analogue, 2-chlor-oadenosine (2 CADO) and N6-cyclopentyladenosine (CPA; A1 adenosine receptor agonist) but not CGS-21680 (A2 a adenosine receptor agonist) induced the expression of HA synthase mRNA, which is responsible for HA production in HGF. These results suggest that intracellular signal (s) via A1 adenosine receptor may play a central role for the upregulation of HA production by activated HGF in inflamed periodontal lesions.These results provide new evidence for the possible involvement of adenosine in the regulation of extracellular matrix production during the course of inflammatory responses in periodontal tissues.

Interleukin-10 as a Regulatory Cytokine Induced by Cellular Stress: Molecular Aspects

Interleukin-10 is an ubiquitous cytokine which plays a major regulatory role in the course of inflammatory responses by downregulating the synthesis of cytokines. In this paper, we summarize the major biological properties of IL-10 and the current knowledge of the molecular mechanisms by which IL-10 inhibits the expression of genes encoding proinflammatory cytokines. We then review the factors upregulating IL-10 synthesis and we present the concept that IL-10 is a stress cytokine produced not only in response to microbial pathogens but also to cellular injuries of diverse origins.

Effects of Ozone Combined with Components of Acid Fogs on Breathing Pattern, Metabolic Rate, Pulmonary Surfactant Composition, and Lung Injury in Rats

AbstractThe pulmonary responses to components of acid fogs, nitric acid, sulfuric acid, and hydroxymethanesulfonate (HMSA), in combination with ozone (O3) were measured to determine if the acid components altered the course of inflammatory responses to the oxidant. Rats were exposed 4 h to 0.4 ppm O3 0.4 ppm O3 + 0.7 mg/m3 HNO3 + 0.6 mg/m3 H2SO4 0.6 mg/m3 HMSA, and 0.4 ppm O3 + 0.5 mg/m3 HMSA. Breathing pattern and metabolic rate were measured during exposure, and fatty acid composition of pulmonary surfactant (PS), nasal epithelial injury, oxidant-induced lung parenchymal lesions, and changes in the total protein in the lavage fluids were measured 23–48 h postexposure. Ozone alone affected all measures except nasal epithelial injury, and the presence of inorganic acids or HMSA in combination with 0.4 ppm O3 did not significantly modify the response to O3 alone. The only response to 0.6 mg/m3 HMSA alone was depression in metabolic rate during exposure. The presence of a pulmonary irritant rapid-shallow br...