Proinflammatory Cytokines

Negative emotions are reliably associated with poorer health (e.g., Kiecolt-Glaser, McGuire, Robles, & Glaser, 2002), but only recently has research begun to acknowledge the important role of positive emotions for our physical health (Fredrickson, 2003). We examine the link between dispositional positive affect and one potential biological pathway between positive emotions and health—proinflammatory cytokines, specifically levels of interleukin-6 (IL-6). We hypothesized that greater trait positive affect would be associated with lower levels of IL-6 in a healthy sample. We found support for this hypothesis across two studies. We also explored the relationship between discrete positive emotions and IL-6 levels, finding that awe, measured in two different ways, was the strongest predictor of lower levels of proinflammatory cytokines. These effects held when controlling for relevant personality and health variables. This work suggests a potential biological pathway between positive emotions and health through proinflammatory cytokines.

Negli ultimi anni si è compreso anche come fattori collegati all'alimentazione e, in generale, allo stile di vita possano essere implicati nell'esacerbazione, nel mantenimento e nella remissione di moltissime malattie; il paradigma della psiconeuroendocrinoimmunologia, a questo proposito, si propone di fornire gli strumenti teorici per indagare il nesso tra le variabili biologiche, psicologiche e comportamentali all'interno di numerose condizioni cliniche (Bottaccioli, 2011). Per realizzare interventi che rispettino il paradigma biopsicosociale appare allora necessario partire dallo studio delle realtà cliniche di interesse in una ottica integrata, tenendo in considerazione sin dall'inizio variabili che comprendano: lo stato psicologico, il livello di stress, le abitudini alimentari e di vita del paziente, proprio alla luce dei modelli integrati proposti.  La letteratura a questo proposito descrive il rapporto tra psoriasi e obesità, tra psoriasi e disturbi del comportamento alimentare, tra psoriasi e diversi tipi di addiction, tuttavia sembra non esista ancora una visione unitaria e integrata di tutti questi fattori, i quali potrebbero influire sulla gravità della patologia cutanea ed agire da fattori di mantenimento. Un lavoro orientato verso questa direzione potrebbe rappresentare quindi una opportunità per accrescere la conoscenza rispetto all'interazione di queste variabili nell'andamento della malattia.

Tumor necrosis factor alpha (TNF-alpha) was discovered more than a century ago, and its known roles have extended from within the immune system to include a neuro-inflammatory domain in the nervous system. Neuropathic pain is a recognized type of pathological pain where nociceptive responses persist beyond the resolution of damage to the nerve or its surrounding tissue. Very often, neuropathic pain is disproportionately enhanced in intensity (hyperalgesia) or altered in modality (hyperpathia or allodynia) in relation to the stimuli. At time of this writing, there is as yet no common consensus about the etiology of neuropathic pain - possible mechanisms can be categorized into peripheral sensitization and central sensitization of the nervous system in response to the nociceptive stimuli. Animal models of neuropathic pain based on various types of nerve injuries (peripheral versus spinal nerve, ligation versus chronic constrictive injury) have persistently implicated a pivotal role for TNF-alpha at both peripheral and central levels of sensitization. Despite a lack of success in clinical trials of anti-TNF-alpha therapy in alleviating the sciatic type of neuropathic pain, the intricate link of TNF-alpha with other neuro-inflammatory signaling systems (e.g., chemokines and p38 MAPK) has indeed inspired a systems approach perspective for future drug development in treating neuropathic pain.

Low socioeconomic status (SES) during childhood confers risk for adverse health in adulthood. Accumulating evidence
suggests that this may be due, in part, to the association between lower childhood SES and higher levels of proinflammatory
cytokines. Drawing from literature showing that low childhood SES predicts exaggerated physiological
reactivity to stressors and that lower SES is associated with a more communal, socially attuned orientation, we
hypothesized that inflammatory reactivity would be more greatly affected by cues of social support among individuals
whose childhood SES was low than among those whose childhood SES was high. In two studies, we found that
individuals with lower subjective childhood SES exhibited greater reductions in pro-inflammatory cytokine reactivity to
a stressor in the presence of a supportive figure (relative to conditions with an unsupportive or neutral figure). These
effects were independent of current SES. This work helps illuminate SES-based differences in inflammatory reactivity
to stressors, particularly among individuals whose childhood SES was low.

The proinflammatory cytokines tumor necrosis factor (TNF) α and interleukin (IL) 1β have been strongly implicated in the pathogenesis of neuropathic pain, but the intracellular signaling of these cytokines in glial cells is not fully understood. TNF receptor-associated factor 6 (TRAF6) plays a key role in signal transduction in the TNF receptor superfamily and the IL-1 receptor superfamily. In this study, we investigated the role of TRAF6 in neuropathic pain in mice after spinal nerve ligation (SNL). SNL induced persistent TRAF6 upregulation in the spinal cord. Interestingly, TRAF6 was mainly colocalized with the astrocytic marker glial fibrillary acidic protein on SNL day 10 and partially expressed in microglia on SNL day 3. In cultured astrocytes, TRAF6 was upregulated after exposure to TNF-α or IL-1β. TNF-α or IL-1β also increased CCL2 expression, which was suppressed by both siRNA and shRNA targeting TRAF6. TRAF6 siRNA treatment also inhibited the phosphorylation of c-Jun N-term...

Inflammatory episodes observed in multiple sclerosis are characterized by perivascular infiltration of central nervous system (CNS) tissue by circulating leucocytes directed by chemokines and activation of both microglia and astrocytes. An in vitro approach, using a three-dimensional aggregate culture system derived from foetal rat brain tissue, is being taken to study the effect of inflammatory mediators on CNS cells. These aggregates model the brain in vivo in terms of glial and neuronal development and cell-cell interactions. Aggregates cultures were treated with lipopolysaccharide (LPS) and the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-α) and interferon-gamma (IFNγ). The effect of these treatments on the expression of a range of chemokine receptors (CCR1, CCR2, CCR5, CXCR3 and CX3CR1) and other markers of cell activation (MHC class I and II, CR3) was determined at the mRNA level by semiquantitative RT-PCR and at the protein level by confocal microscopy. Rat peritoneal macrophages were loaded with a fluorescent cell-tracer and their ability to infiltrate inflamed aggregates treated with IFNγ was analysed by FACS and confocal microscopy.

The depressive state has been characterised as one of elevated inflammation, which holds promise for better understanding treatment-resistance in affective disorders as well as for future developments in treatment stratification. Aiming to investigate alterations in the inflammatory profiles of individuals with depression as putative biomarkers for clinical response, we conducted meta-analyses examining data from 35 studies that investigated inflammation before and after treatment in depressed patients together with a measure of clinical response. There were sufficient data to analyse IL-6, TNFα and CRP. Levels of IL-6 decreased with antidepressant treatment regardless of outcome, whereas persistently elevated TNFα was associated with prospectively determined treatment resistance. Treatment non-responders tended to have higher baseline inflammation, using a composite measure of inflammatory markers. Our findings suggest that elevated levels of inflammation are contributory to treatment resistance. Combining inflammatory biomarkers might prove a useful tool to improve diagnosis and detection of treatment refractoriness, and targeting persistent inflammation in treatment-resistant depression may offer a potential target for the development of novel intervention strategies.

When activated through toll-like receptors (TLRs), macro-phages generate IL-33, an IL-1 family member that induces innate immune responses through ST2 signaling. LPS, a TLR4 ligand, induces macrophages to generate prostaglandin E 2 (PGE 2) through inducible COX-2 and microsomal PGE 2 syn-thase 1 (mPGES-1) (1). We demonstrate that IL-33 production by bone marrow-derived murine macrophages (bmMFs) requires the generation of endogenous PGE 2 and the intrinsic expression of EP 2 receptors to amplify NF-B-dependent, LPS-induced IL-33 expression via exchange protein activated by cAMP (EPAC). Compared with WT cells, bmMFs lacking either mPGES-1 or EP 2 receptors displayed reduced LPS-induced IL-33 levels. A selective EP 2 agonist and, to a lesser extent, EP 4 receptor agonist potentiated LPS-induced IL-33 generation from both mPGES-1-null and WT bmMFs, whereas EP 1 and EP 3 receptor agonists were inactive. The effects of PGE 2 depended on cAMP, were mimicked by an EPAC-selective agonist, and were attenuated by EPAC-selective antagonism and knockdown. LPS-induced p38 MAPK and NF-B activations were necessary for both IL-33 production and PGE 2 generation, and exogenous PGE 2 partly reversed the suppression of IL-33 production caused by p38 MAPK and NF-B inhibition. Mice lacking mPGES-1 showed lower IL-33 levels and attenuated lung inflammation in response to repetitive Alternaria inhalation challenges. Cumulatively, our data demonstrate that endogenous PGE 2 , EP 2 receptors, and EPAC are prerequisites for maximal LPS-induced IL-33 expression and that exogenous PGE 2 can amplify IL-33 production via EP 2 and EP 4 receptors. The ubiquitous induction of mPGES-1-dependent PGE 2 may be crucial for innate immune system activation during various IL-33 driven pathologic disorders. IL-33 is a recently discovered member of the IL-1 cytokine family that binds to TLR/IL1R 2 superfamily receptor ST2 (2– 4). IL-33 is constitutively expressed in the nuclei of epithe-lial cells at barrier sites such as the skin, lung, and intestine and is also expressed by fibroblastic reticular cells and endothelial cells within lymphoid tissues (5). It interacts with histones, promotes chromatin compaction, and retards NF-B transcrip-tional activity (5). It can also be released in response to cellular damage or activation and, after proteolytic processing to an active cytokine, can bind to a heterotrimeric receptor composed of T1/ST2 and IL-1RAcP, influencing both innate and adaptive type 2 immune responses (2). In addition to barrier cells, macrophages and dendritic cells can inducibly express IL-33 and contribute to the amplification of inflammatory responses in sepsis, cardiovascular disease, and allergy (6 –9). However, little is known about the mechanisms that control such inducible IL-33 expression. Among the resident hematopoietic cells involved in innate immunity, macrophages are noteworthy for inducible expression of IL-33 in response to LPS in vitro (10 –12) and also upon infection with H3N1 or by TLR7/8 agonist stimulation (13). These same stimuli also induce macrophages to generate pros-taglandin E 2 (PGE 2), a lipid mediator that plays critical roles in pyrexia, pain sensation, and inflammation. LPS-stimulated macrophages generate PGE 2 from endogenous arachidonic acid that is converted sequentially to prostaglandin H 2 (PGH 2) and then to PGE 2 , primarily by the inducible enzymes COX-2 and microsomal PGE 2 synthase 1 (mPGES-1), respectively (1). When released, PGE 2 acts through four types of E prostanoid receptors (EP 1-EP 4) and can function as both autocrine as well as paracrine mediators (14). In addition to generating PGE 2 , macrophages also express EP receptors and respond to endog-enous and exogenous PGE 2 ex vivo. In particular, by eliciting signaling through cAMP and PKA-dependent transcription factors, PGE 2 can amplify the production of IL-6 by macro-phages and of IL-23 by dendritic cells but can also suppress the generation of IL-23 and IL-12 by human monocytes. Although exogenous PGE 2 can potentiate IL-33 expression by dendritic

Mast cells (MCs) derive from a distinct precursor in the bone marrow and are predominantly found in tissues at the interface between the host and the external environment where they can secrete mediators without overt degranulation. Mast cells mature under local tissue microenvironmental factors and are necessary for the development of allergic reactions, through crosslinking of their surface receptors for IgE (FcεRI), leading to degranulation and the release of vasoactive, pro-inflammatory and nociceptive mediators that include histamine, pro-inflammatory and anti-inflammatory cytokines and proteolytic enzymes. Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demylination within the central nervous system. MCs are involved in the pathogenesis of MS by generating various vasoactive mediators and cytokines and participate in the destruction of the myelin sheath and the neuronal cells. The process of the development of demyelinating plaques in MS is proba...

OBJECTIVES:
In this study, a newly synthesized cytokine inhibitor FR167653 was investigated using a rat heart ischemia-reperfusion model to prove its myocardial protective effect and its role in the inhibition of cytokine production in ischemic myocardium.

METHODS:
Studies were performed with isolated, Langendorff-perfused Lewis rat hearts (n=80) which were either treated with FR167653 or untreated, as the control group, and subjected to ischemia-reperfusion.

RESULTS:
Reperfusion followed by 30min of 37 degrees C ischemia induced marked myocardial cytokine expression and activated p38MAPK. FR167653 administered before ischemia and during reperfusion significantly reduced ischemia-activated myocardial TNFalpha mRNA expression (190+/-97 vs. 4805+/-3017, P=0.024) as well as TNFalpha production (0 vs. 9.6+/-2.5 ng/ml, P<0.05) and also inhibited p38 MAPK activation. Its administration improved recovery of cardiac contractile function during reperfusion: LVDP (130+/-18 vs. 82+/-21 mmHg (P=0.002)), max/min dP/dt (2812+/-328/-2283+/-216 vs. 1520+/-424/-1325+/-237 mmHg/s, P=0.003). CPK leakage was significantly reduced in FR167653 treated hearts versus untreated hearts (54+/-6 vs. 0.5+/-0.1, P<0.05) and reduction of coronary flow was improved (110+/-13 vs. 77+/-11%) 1h after beginning of reperfusion (P<0.05). Moreover, FR administration attenuated the number of TUNEL positive cardiomyocytes (3+/-1 vs. 9+/-2%).

CONCLUSION:
These data demonstrated positive inotropic and antiapoptotic effects of a newly synthesized compound (FR167653) of cytokine inhibitors and its inhibitory effect on myocardial TNFalpha production and p38 MAPK activation in ischemic-reperfused rat heart. This suggested that cytokine inhibition is significant as a method for myocardial protection against ischemia-reperfusion injury.

PMID: 15519192

In response to social-evaluative threat induced in the laboratory, lower (compared to higher) subjective
social class of a participant predicts greater increases in the inflammatory cytokine interleukin-6 (IL-6).
In spite of the interpersonal nature of social-evaluation, little work has explored whether characteristics
of the evaluator shape physiological responses in this context. In the current study, in a sample of 190 college
students (male = 66), we explored whether one’s subjective social class interacts with the perceived
social class of an evaluator to predict changes in Oral Mucosal Transudate (OMT) IL-6 in response to the
Trier Social Stress Test (TSST). Participants were randomly assigned to be the speaker or the evaluator.
Extending past work, we found that while speakers low in subjective social class consistently respond
with strong increases in IL-6 regardless of their perception of their evaluator’s social class, speakers high
in subjective social class responded with greater increases in IL-6 when their evaluator was perceived as
high social class compared to when they were perceived as low social class. This finding highlights the
importance of perceptions of the evaluator in informing inflammatory responses to a social-evaluative
task.

J Thromb Haemost. 2011 Aug;9(8):1452-9. doi: 10.1111/j.1538-7836.2011.04415.x.


Abstract
BACKGROUND: CD40 ligand(CD40L) is implicated in atherosclerotic plaque formation.

OBJECTIVES: We investigated prospective associations between circulating soluble CD40L and myocardial infraction (MI) or stroke in an older general population cohort, accounting for established and novel cardiovascular risk factors.

METHODS: Baseline serum CD40L (sCD40L) was measured in incident MI (n = 368) and stroke (n = 304) cases and two controls per case, 'nested' in prospective UK studies of 4252 men and 4286 women aged 60-79 years, sampled from general practices in Britain in 1998-2000, with 7-year follow-up for fatal and non-fatal MI and stroke.

RESULTS: sCD40L was higher in smokers and negatively associated with lung function and positively associated with total cholesterol and markers of inflammation, but not with other established cardiovascular disease (CVD) risk factors. Geometric mean sCD40L levels did not differ between MI cases and controls (5.94 ng mL(-1) vs. 5.82 ng mL(-1); P = 0.5) or between stroke cases and controls (5.61 ng mL(-1) vs. 5.28 ng mL(-1), P = 0.1). There was no strong evidence for elevated risk of MI or stroke in multivariable models comparing participants in the top to those in the bottom third of sCD40L. Age-adjusted odds ratios (ORs) were 1.39 [95% confidence interval (CI) 0.98, 1.96] for MI and 1.16 (0.78, 1.73) for stroke. These attenuated to 1.24 (95% CI 0.86, 1.79) and 1.18 (0.78, 1.78), respectively, after adjustment for established and novel CVD risk factors.

CONCLUSIONS: sCD40L is associated with other inflammatory markers but is not itself a strong independent risk marker for either stroke or MI.

© 2011 International Society on Thrombosis and Haemostasis.

PMID:21696538[PubMed - in process]

Keywords: CD40, coronary heart disease, epidemiology, myocardial infarction, prospective study, stroke.

a Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, United Kingdom b Leukocyte Biology Section, National Heart and Lung Institute, Imperial College, South Kensington, London SW7 2AZ, United Kingdom c Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, Whitechapel, London E1 2AT, United Kingdom

The relevance of the study is in the fact that disorders of vascular and psychoneuroendocrine genesis often accompany surgical diseases, the issue of ensuring patient safety in the perioperative period remains the basic focus of modern clinical surgery. The purpose of the study is to identify changes in the level of pro-inflammatory cytokines and the functional state of the endothelium, and also to establish whether the transferred simultaneous surgical interventions intensified pro-inflammatory cytokines and changes in the functional state of the endothelium. In this article, changes in the level of proinflammatory cytokines and the functional state of the endothelium are studied, as well as the relationship of these changes with comorbid psychoemotional disorders when performing simultaneous surgical interventions by laparoscopic and open methods in combined diseases of organs of the abdominal and anterior abdominal wall. The authors carried out a prospective, randomized controlled study of 586 patients aged 18 to 72 years who underwent planned simultaneous surgical intervention (SSI) with combined diseases of the abdominal cavity, pelvis and anterior abdominal wall. In the course of the comparative analysis, a general trend was established: the simultaneous surgical interventions caused intensification of proinflammatory cytokines and changes in the functional state of the endothelium.

The purpose of this study was to investigate a role of heat shock transcription factor 1 (HSF1)-mediated stress response during regeneration of injured soleus muscle by using HSF1-null mice. Cardiotoxin (CTX) was injected into the left muscle of male HSF1-null and wild-type mice under anesthesia with intraperitoneal injection of pentobarbital sodium. Injection of physiological saline was also performed into the right muscle. Soleus muscles were dissected bilaterally 2 and 4 weeks after the injection. The relative weight and fiber cross-sectional area in CTX-injected muscles of HSF1-null, not of wild-type, mice were less than controls with injection of physiological saline 4 weeks after the injury, indicating a slower regeneration. Injury-related increase of Pax7-positive muscle satellite cells in HSF1-null mice was inhibited versus wild-type mice. HSF1-deficiency generally caused decreases in the basal expression levels of heat shock proteins (HSPs). But the mRNA expression levels o...

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a novel coronavirus in late 2019, since then it is infecting people and spreading efficiently among humans worldwide, causing the infectious disease named coronavirus disease 2019 (COVID-19). Some patients infected with SARS-CoV-2 develop severe inflammatory‐induced lung injury as a result of a cytokine storm syndrome (CSS), which may cause acute respiratory distress syndrome (ARDS), the main cause of mortality in SARS-CoV-2 patients. Tumor necrosis factor alpha converting enzyme (TACE) controls by ectodomain shedding the bioavailability and release of various cell surface bound signaling molecules, many of them are inflammation mediators, as the cytokine TNFα, one of the molecules most affected by TACE.

In severely or critically ill patients, the host immune response to the SARS-CoV-2 infection is hyperactive, resulting in an excessive inflammatory response, forcing TACE to hyperexcitability proteolytic activity state. This TACE over-induction state results in aberrant ectodomain shedding of multitude of TACE membrane-bound substrates, releasing massive amount of cytokine TNF-α and other inflammation mediators, that may trigger more inflammation in those patients leading to CSS, cellular dysfunction, cell death, and tissue damage and ARDS. Over-induction of TACE activity may be attenuated by temporarily targeting TACE with specific inhibitors that significantly decrease tissue and plasma levels of circulating proinflammatory cytokines.

This research corresponds to virtual screening of FDA-approved drug library and molecular modeling analysis of selected drugs in the experimental crystal structure of TACE. This study reveals that rosiglitazone and pioglitazone, two already approved therapeutic agents to treat type II diabetes, were found to bind favorably to TACE catalytic site with highlighted binding features. These results suggest rosiglitazone and pioglitazone thus might open a new potential therapeutic approach toward the drug repurposing of these thiazolidinediones for temporally and specifically inhibit TACE to treat SARS-CoV-2 infection-associated aberrant systemic inflammatory response and, consequently, to diminish tissue damage and death rates associated with CSS and ARDS among SARS-CoV-2 patients. This study provides scientific information for the selection of rosiglitazone and pioglitazone to be further validated in vivo.

Purpose This study aimed to assess the effect of diurnal intermittent fasting (DIF) during and outside of the month of Ramadan on plasma levels of interleukin (IL)-1β, IL-6, and IL-8, while controlling for sleep/wake pattern, sleep length and quality, meal composition, energy consumption and expenditure, and light exposure. DIF outside of the month of Ramadan was performed to evaluate the effect of DIF in the absence of the way of life accompanying Ramadan. Methods Twelve healthy male volunteers with a mean age of 25.1 ± 2.5 years arrived to the sleep laboratory on 4 times: 1) adaptation, 5 weeks before Ramadan; 2) 4 weeks before Ramadan while performing DIF for 1 week (fasting outside of Ramadan; FOR); 3) 1 week before Ram-adan (non-fasting baseline; non-fasting BL); and 4) After completing 2 weeks of Ramadan while performing DIF. Plasma levels of cytokines were assessed using enzyme-linked

Fucoidan is a highly sulfated glycosaminoglycan, which has a molecular structure similar to that of heparin. The antithrombotic effects of fucoidan in vitro have been widely reported, but its antithrombotic effects in vivo as well as its other biological properties in vitro have not been well investigated. This study investigated the effects and mechanism of fucoidan from Fucus vesiculosus on thrombosis both in vitro and in vivo. A ferric chloride-induced mouse carotid artery thrombosis model was used to determine the antithrombotic effects of fucoidan in vivo. Additionally, changes in the levels of proinflammatory cytokines and chemokines were examined in vascular cells treated with fucoidan. In vivo studies employing a ferric chloride-induced mouse carotid artery thrombosis model indicated that fucoidan had a stronger antithrombotic activity than heparin. Further, vascular cells treated with fucoidan demonstrated a decrease in proinflammatory cytokine and chemokine production as w...