Hyperproduction Of Proinflammatory Cytokines Research Articles

Chronic Non-Bacterial («Sterile») Osteomyelitis in the Practice of Pediatric Rheumatologist, the Contemporary Diagnostic and Treatment Approaches: Literature Review and Own Data Analysis

The article presents the current data on the pathogenesis, features of clinical manifestations, and diagnostics of different variants of chronic non-bacterial («sterile») osteomyelitis (CNO). The inherited forms of the disease, such as syndromes of deficiency of the interleukin-1 receptor antagonist (DIRA), sterile pyarthrosis with pyoderma gangrenosum and acne (PAPA-syndrome), dyserythropoietic anemia with chronic non-bacterial osteomyelitis (Majeed-syndrome) are described. The pathogenesis of CNO and related diseases is based on hyperproduction of proinflammatory cytokines, particularly of interleukin-1 β and tumor necrosis factor- α . Based on the literature data and our own observations, the recommendations for diagnostics and treatment of CNO are presented.

Role of Triggering Receptor Expressed on Myeloid Cells in the Activation of Innate Immunity

The innate immune system plays a key role in triggering a systemic inflammatory response (SIR). The triggering receptor expressed on myeloid cells (TREM-1), which is located on neutrophils and monocytes, is involved in SIR, by regulating the effector mechanisms of innate immunity. Hyperproduction of proinflammatory cytokines is a pathogenetic component of the hyperergic phase of acute systemic inflammation. The simultaneous activation of Toll-like receptors and TREM-1 increases the production of cytokines manifold. This is compensatory and adaptive, however, resulting in damage to organs and tissues during excessive production of cytokines. Key words: triggering receptor expressed on myeloid cells, Toll-like receptors, cytokines, inflammation.

Glycogen synthase kinase 3 involvement in the excessive proinflammatory response to LPS in patients with decompensated cirrhosis

In decompensated cirrhosis, the early innate immune response to the Toll-like receptor 4 (TLR4) agonist, lipopolysaccharides (LPS), is characterized by a hyper-production of pro-inflammatory cytokines and hypo-production of the anti-inflammatory cytokine IL-10. In LPS-stimulated non-cirrhotic immune cells, the constitutively active glycogen synthase kinase (GSK) 3 favors pro- vs. anti-inflammatory cytokines, by acting on gene induction. However, in these cells, TLR4 dampens its own pro-inflammatory response by inducing early (within minutes) AKT-mediated phosphorylation of GSK3β (one of two GSK3 isoforms) on Ser9. Phosphorylation of GSK3β (Ser9) inhibits its activity, decreases pro-inflammatory cytokines, and increases IL-10. Thus, we investigated the role of GSK3 in LPS-induced cytokine production by peripheral blood mononuclear cells (PBMCs) or monocytes from patients with advanced cirrhosis and normal subjects. Cells were pre-incubated with or without GSK3 inhibitor (SB216763 or lithium chloride) for 1h and then stimulated with LPS. Cytokine production was assessed at mRNA and secreted proteins levels, by real-time RT-PCR at 1h and ELISA at 20 h, respectively. GSK3β phosphorylation was assessed using Western blotting. In cirrhotic and normal PBMCs pretreated with GSK3 inhibitors, LPS-induced production of pro-inflammatory proteins TNF-α and IL-12p40 was significantly decreased while that of IL-10 was increased. LPS-induced, AKT-mediated phosphorylation of GSK3β on Ser9 found in normal monocytes, was abolished in cirrhotic cells. GSK3 is involved in the early TLR4-mediated pro-inflammatory response in patients with decompensated cirrhosis. This was associated with a defect in AKT-mediated GSK3β phosphorylation resulting in unrestricted 'pro-inflammatory' activity of the enzyme.

Some Aspects of Formation of a Systemic Inflammatory Response in Critically Ill Patients

Objective: to study the general regularities and pathogenetic significance of changes in primary and secondary inflammatory mediator ratios in the formation of a systemic inflammatory response in critically ill patients. Subjects and methods. Three hundred and eighty-seven critically ill inpatients from intensive care units were examined. Results. The systemic inflammatory response syndrome develops in critical conditions, which is characterized by the increased serum levels of primary (proinflammatory cytokines) and secondary (C-reactive protein, fibrinogen) inflammatory mediators, which was more substantial in infected patients. When the hyperproduction of proinflammatory cytokines was evident, there was no adequate proinflammatory response, as suggested by the negative IL-10 level changes. Correlations were established between the serum content of inflammatory mediators and the indices of external respiration function, respiration rate, and heart rate. Conclusion. The nature of changes in the quantitative (mediator concentrations) and qualitative (mediator ratio) indices enables one to estimate the intensity of a systemic inflammatory response and to predict its further progression. Key words: critical condition, systemic inflammatory response, inflammatory mediators.

The Role of Immune Reconstitution in the Onset of Subclinical Atheromasic Lesions

To the Editors: In recent studies,1-3 patients with low CD4+ cell count showed an increased risk for cardiovascular disease (CVD). A hyperproduction of proinflammatory cytokines (interleukin-6, high sensitivity C-reactive protein [hsPCR]) have been hypothesized in these patients.4 Few data exist regarding the role of immune reconstitution in the onset of CVD, another condition that could be related to an increase of circulating proinflammatory factors. Aimed at the detection of subclinical atheromasic lesions in patients who experienced immune reconstitution, in the present study, we evaluated 263 patients starting antiretroviral therapy (ART) at baseline and after 12 months, with color Doppler ultrasonography of the epiaortic vessels, a well-validated technique, considered the gold standard for the detection of premature vascular lesions. The patients were subjected to color Doppler ultrasonography of the epiaortic vessels using a last-generation power color Doppler instrument with 7.5 mgHz probes (ACUSON sequoia 512). Ultrasonography was performed by physicians specifically trained on carotid vessels and had at least 15 years experience with the ultrasound color Doppler technique and about 10,000 documented epiaortic examinations. They were blinded to the patient's treatment history and status and unaware of the diagnosis of the other colleagues. The patients were placed in a supine position after at least 10 minutes of acclimatization in a comfortable room. They were informed that the investigation was noninvasive. The 2 common carotids, the bifurcations and at least the first 2 cm of the internal and external carotid vessels were examined in the short and long axis during the telediastolic phase (T wave of the electrocardiogram). During the investigation, the head of the patient was hyperextended and extrarotated from the opposite side. The morphological investigation of the plaques was performed using both ultrasonography and the ultrasound power color Doppler to better characterize the profile of the plaque and the intima media thickness. An intima media thickness >0.9 mm and/or the presence of atherosclerotic plaques were considered pathologic findings. After 12 months of ART, patients with <50 CD4+ cell count per cubic millimeter at baseline were divided into 3 groups based on CD4+ at follow-up: group A: patients with <100 CD4+ (# 41); group B: patients with 100-200 CD4+ (# 50); and group C: patients with >200 CD4+ (# 62). The CD4+ cell count was detected on 2 separate occasions, measured sequentially at least 4 weeks apart. The data were compared with those observed in 110 patients starting their ART with >200 CD4+ and remaining at follow-up, over this value (group D). The 4 groups were comparable for gender, mean age, and other risk factors for CVD. All patients were treated with a PI-based therapy. Backbone drugs were well balanced among the groups (Table 1). Statistical analysis was performed using χ2 test. The Ethics Committee of the hospital approved the study, and the patients provided informed consent.TABLE 1: Distribution of Demographics, Risk Factors for CVD, and Antiretroviral Therapies Among the GroupsAs showed in Figure 1, patients with <50 CD4+ cell count at baseline that reached values >200 (group C) showed a significant increase in the number of carotid lesions at follow-up. Moreover, comparing patients with <50 cells at baseline (groups A + B + C) with patients with >200 cells (group D), the first group had a significant increase of lesions with respect to group D (P = 0.00001).FIGURE 1: Distribution of subclinical carotid lesions at baseline and at follow-up with statistical analysis.In a previous issue, Williams et al5 observed a higher rate of myocardial infarctions and other symptomatic cardiovascular events in patients experiencing immune reconstitution. Our data show that patients starting ARV with a high degree of immune depression tend to develop more subclinical carotid lesions with respect to patients starting ARV in a relatively better immunologic condition. Moreover, patients experiencing a more rapid immune reconstitution develop a significantly higher number of subclinical vascular lesions. These data suggest that inflammatory events characterizing both immune deficiency and immune reconstitution could play a role in the onset of CVD. Paolo Maggi, MD* Anna Volpe, BD* Chiara Bellacosa, MD* Giuseppe Pastore, MD* Francesco Perilli, MD† Antonio Lillo, MD† Guido Regina, MD† *Clinica delle Malattie Infettive, Università degli Studi di Bari, Italy †Cattedra di Chirurgia Vascolare, Università degli Studi di Bari, Italy

Prophylactic ciprofloxacin treatment prevented high mortality, and modified systemic and intestinal immune function in tumour-bearing rats receiving dose-intensive CPT-11 chemotherapy

Infectious complications are a major cause of morbidity and mortality from dose-intensive cancer chemotherapy. In spite of the importance of intestinal bacteria translocation in these infections, information about the effect of high-dose chemotherapy on gut mucosal immunity is minimal. We studied prophylactic ciprofloxacin (Cipro) treatment on irinotecan (CPT-11) toxicity and host immunity in rats bearing Ward colon tumour. Cipro abolished chemotherapy-related mortality, which was 45% in animals that were not treated with Cipro. Although Cipro reduced body weight loss and muscle wasting, it was unable to prevent severe late-onset diarrhoea. Seven days after CPT-11, splenocytes were unable to proliferate (stimulation index=0.10±0.02) and produce proliferative and inflammatory cytokines (i.e., Interleukin (IL)-2, interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α) IL-1β, IL-6) on mitogen stimulation in vitro (P<0.05 vs controls), whereas mesenteric lymph node (MLN) cells showed a hyper-proliferative response and a hyper-production of pro-inflammatory cytokines on mitogen stimulation. This suggests compartmentalised effects by CPT-11 chemotherapy on systemic and intestinal immunity. Cipro normalised the hyper-responsiveness of MLN cells, and in the spleen, it partially restored the proliferative response and normalised depressed production of IL-1β and IL-6. Taken together, Cipro prevented infectious challenges associated with immune hypo-responsiveness in systemic immune compartments, and it may also alleviate excessive pro-inflammatory responses mediating local gut injury.

Burkholderia pseudomallei aerosol infection results in differential inflammatory responses in BALB/c and C57Bl/6 mice

Melioidosis is caused by the Gram-negative bacterium Burkholderia pseudomallei, whose portals of entry into the body include subcutaneous, ingestion and inhalation routes. Animal models play an important role in furthering our understanding of this disease, which is associated with high morbidity and mortality in susceptible subjects. Previous studies using intranasal inoculation showed a differential susceptibility to inhalational melioidosis in BALB/c and C57Bl/6 mice and attributed the difference to genetic factors and host response. However, a recent study found no difference in susceptibility when the two species of mice were exposed to nebulized bacteria. We sought to address this discrepancy by using a nasal route only, instead of whole-body aerosol exposure system. Employing three different clinical strains of B. pseudomallei and following the progression of disease development in both BALB/c and C57Bl/6 mice, we found that BALB/c mice were at least 10- to 100-fold more susceptible to infection than C57Bl/6 mice. Comparison of bacterial burdens in aerosol-challenged mice, at both the pulmonary and distant sites of infection, suggests that C57Bl/6 mice were more efficient in clearing the bacteria than BALB/c mice. In addition, a comprehensive study of a wide panel of chemokines and cytokines at the protein level demonstrated that hyperproduction of proinflammatory cytokines in aerosol-challenged BALB/c mice did not translate into better protection and survival of these mice, whereas a moderate increase in these proteins in aerosol-challenged C57Bl/6 mice was more beneficial in clearing the infection. This suggests that high levels of proinflammatory cytokines are detrimental and contribute to the immunopathogenesis of the infection.

Fisiopatología de la translocación y la peritonitis bacteriana espontánea en la cirrosis

El mecanismo patogénico clave que inicia la peritonitis bacteriana espontánea (PBE) es la translocación bacteriana (TB), proceso por el cual las bacterias entéricas cruzan la barrera mucosa intestinal e infectan los ganglios linfáticos mesentéricos, y desde donde alcanzan la circulación sanguínea y, posteriormente, el líquido ascítico. La alta tasa de TB en la cirrosis se debe al daño en los 3 pilares que constituyen la barrera mucosa del intestino: equilibrio de la flora bacteriana intraluminal, integridad de la barrera epitelial intestinal y sistema inmunitario local. La diseminación sanguínea y el crecimiento de los gérmenes en el líquido ascítico que se produce en la PBE es consecuencia del daño en el sistema inmunitario que conlleva la cirrosis. La hiperproducción en el líquido ascítico de citocinas proinflamatorias y otras sustancias con propiedades vasoactivas contribuye a la vasodilatación arterial y a la insuficiencia renal que, con frecuencia, complica el curso de la PBE. Aun en ausencia de PBE, la translocación de bacterias y productos bacterianos desde la luz intestinal contribuye a la activación sistémica de las células inmunitarias en la cirrosis. The key pathogenic mechanism initiating spontaneous bacterial peritonitis (SBP) is bacterial translocation (BT), a process through which enteric bacteria cross the intestinal barrier and infect the mesenteric lymph nodes, thus entering the blood circulation and ascitic fluid. The high rate of bacterial translocation in cirrhosis is due to injury to the three pilars composing the intestinal mucosal barrier (the balance of intraluminal bacterial flora, the integrity of the intestinal epithelial barrier, and the local immune system). Blood dissemination and microbial growth in ascitic fluid resulting from SBP are a consequence of damage to the immune system in cirrhosis. Hyperproduction of proinflammatory cytokines and other vasoactive substances contributes to the arterial vasodilation and renal failure that frequently complicate the course of SBP. Even in the absence of SBP, translocation of bacteria and bacterial products from the intestinal lumen contribute to systemic inactivation of immune cells in cirrhosis.

Effects of antidepressants on the production of cytokines.

There is now evidence that major depression is associated with an up-regulation of the inflammatory response system (IRS). One of the major factors in this IRS activation is the hyperproduction of pro-inflammatory cytokines. Recently, a number of studies examined whether there is a causative role of these inflammatory mediators in the aetiology of major depression. Studies with animal models and cytokine immune therapy in humans suggest that pro-inflammatory cytokines induce depressive symptomatology. Moreover, these depressive symptoms can be effectively reversed by antidepressant treatment. Thus, it may be suggested that antidepressants suppress pro-inflammatory cytokine production and/or action, resulting in improvement of depressive symptoms. The influence of antidepressants on cytokine production has been examined in culture systems in vitro, and in animal models of depression - in which cytokine production is induced by endotoxin administration. Results suggest that antidepressants of several classes decrease the production of pro-inflammatory cytokines such as interferon-gamma and tumour necrosis factor-alpha, and increase that of interleukin-10, an anti-inflammatory cytokine. Further, the effect of antidepressive treatment on cytokine secretion and on plasma levels of cytokines in depressed patients has been studied. Unfortunately, different approaches to examine cytokine production and different techniques to measure cytokines in plasma are used in these studies. Despite this, current data indicate a normalization of cytokine plasma levels and cytokine production after antidepressant treatment. It is clear, however, that more research is warranted and we strongly argue the need for higher standardization in the methodology used to examine the cytokine network in depressed patients.

Peripheral blood lymphocyte subsets in acute human melioidosis.

[Extract] Melioidosis is a gram-negative bacterial infection caused by Burkholderia pseudomallei. Although it often occurs in individuals with coexistent disease predisposing to immunosupression, it also occurs in apparently normal individuals [1]. As it has been shown to be a facultative intracellular pathogen [2], it can therefore evade many of the normal immunological defence mechanisms. However, its pathogenesis remains poorly understood. In human melioidosis clinical studies have demonstrated elevation of TNF-alpha [3], IFN-gamma, IL-2 [4], IL-6, and IL-10 [3] as well as other cytokines and chemokines. Hyperproduction of proinflammatory cytokines is associated with lethality [3]. Studies using a mouse model have (i) shown that eradication of Burkholderia pseudomallei in vitro requires the interaction of cells of the monocyte series with lymphocytes [5], (ii) have demonstrated the absolute dependence of resistance to Burkholderia pseudomallei on IFN-gamma [6], and (iii) shown that NK cells and CD8+ lymphocytes are the sources of this IFN-gamma [7]. In view of these findings, reduction in lymphocyte numbers or function may be important for the survival of this pathogen.