Interleukin-10: potential benefits and possible risks in clinical infectious diseases

Human interleukin-10 (IL-10) is a potent anti-inflammatory cytokine that inhibits the synthesis of the major proinflammatory cytokines and chemokines. IL-10 is the principal TH2-type cytokine that upregulates humoral immune responses and attenuates cell-mediated immune reactions. This cytokine has a number of immunomodulatory properties that might be clinically useful in a variety of inflammatory and infectious disease states. Clinical trials with human recombinant IL-10 are already in progress. Carefully selected patients with inflammatory conditions may benefit from IL-10 therapy if concomitant infectious diseases are recognized and treated appropriately.     

Synergistic effect of immunoregulatory cytokines on peripheral blood monocytes from patients with inflammatory bowel disease

Active inflammatory bowel disease (IBD) is characterized by increased monocyte secretion of proinflammatory cytokines. Immunoregulatory cytokines such as Interleukin (IL)-4, IL-10, and IL-13 are capable of inhibiting the proinflammatory cytokine response of activated monocytes. The aim of our study was to determine the effect of different antiinflammatory cytokines under various culture conditions and to evaluate combinations of antiinflammatory cytokines in down-regulating monocyte response in IBD. Peripheral monocytes from patients with active IBD were isolated and stimulated with pokeweed mitogen (PWM). IL-4, IL-10, IL-13 and a combination of IL-4/IL-10 and IL-10/IL-13 were added at different concentrations and different times. Secretion of IL-1beta and TNF-alpha was assessed using sandwich ELISA systems. There was a diminished down-regulation of TNF-alpha by IL-4 and IL-13 in IBD when the cytokines were added at the time of stimulation, while there was a significantly higher down-regulation when monocytes were primed with these Th-2 cytokines 24 hr before activation. IL-10 plus IL-4 and IL-10 plus IL-13, respectively, inhibited the proinflammatory cytokine response of monocytes as well as matured macrophages much more than IL-4, IL-10, or IL-13 alone. Even at suboptimal concentrations for each cytokine alone, a combination of cytokines showed synergistic inhibitory effects. In summary, a combination of antiinflammatory cytokines is more effective in down-regulating the response of activated monocytes than using the cytokines alone and thus may have a potential therapeutic benefit for patients with IBD.     

Current topics in the regulation of prostanoids--2. The interaction with cytokines and nitric oxide

Cyclooxygenase (COX)-2 is induced by proinflammatory cytokines such as interleukin (IL)-1 beta, cytokines produced from helper T cell subpopulation Th 1, such as interferon-gamma and tumor necrosis factor-beta. Cytokines produced by the T cell such as IL-4, IL-10, and IL-13 down-regulate induction of COX-2. The novel MAP kinase pathway, JNK and/or p 38, are important intracellular signaling pathways for induction of COX-2. The increased production of prostaglandin E2 by upregulation of COX-2 increases IL-6 production. By utilizing a COX-2 blocker, it is possible to decrease IL-6 production via reduction of prostanoid production, thereby attenuating the systemic inflammatory response. Nitric oxide (NO) and prostanoids are also known to interact and regulate each other. It is important to note the interactions between prostanoids and cytokines or other inflammatory mediators such as NO in understanding the mechanism of the anti-inflammatory effects of prostanoid regulation.     

Serial prognostic capabilities of electrocardiographic indices of infarcted and hibernating myocardium in predicting short- and long-term outcome following coronary artery bypass surgery

Concentrations and ex vivo production of interleukin 1 beta (IL-1), tumour necrosis alpha (TNF), interleukin 6 (IL-6), interleukin-1 receptor antagonist (IL-1RA) and TNF soluble receptors (sTNF-receptors, P55 and P75) were measured in bronchoalveolar lavage (BAL) fluid and blood in 23 HIV-seropositive (HIV+) patients with Pneumocystis carinii pneumonia (PCP) and compared with values found in healthy HIV-seronegative (HIV-) controls and asymptomatic HIV+ subjects. Concentrations of the proinflammatory cytokine IL-1 beta were increased in BAL fluid of HIV+ patients with PCP (184 +/- 47 pg mL-1) compared with undetectable levels in healthy control subjects (P = 0.0001). In plasma of these patients higher concentrations of the anti-inflammatory cytokine IL-1RA were found during acute PCP than after recovery (2.1 +/- 0.7 vs. 0.5 +/- 0.2 ng mL-1, P = 0.01). No correlations could be found between cytokine concentrations and clinical severity of the infection. Corticosteroid treatment did not influence cytokine concentrations in BAL or blood, nor did it suppress the production in alveolar cells. In whole-blood cultures, however, lipopolysaccharide (LPS)-stimulated production was significantly suppressed for IL-1 (1.3 vs. 5.5 ng mL-1, P = 0.009) and for IL-6 (0.6 vs. 2.5 ng mL-1, P = 0.01). The overall data show that in HIV+ patients with PCP (similar to what we had found previously in HIV-patients with PCP) proinflammatory cytokines are more prominently present in BAL, whereas anti-inflammatory reaction is predominant in the circulation.     

Intrathecal release of pro- and anti-inflammatory cytokines during stroke

A growing body of evidence points out the potential role of inflammatory mechanisms in the pathophysiology of ischaemic brain damage. We have recently demonstrated that stroke patients display an intrathecal production of proinflammatory cytokines, such as IL-1beta and IL-6 already within the first 24 h after the beginning of symptoms (Tarkowski et al., 1995). The aim of the present study was to investigate patterns of local inflammatory responses as a consequence of acute stroke. Thirty stroke patients were studied prospectively on days 0-3, 7-9, 21-26 and after day 90 with clinical evaluations, radiological assessments and analysis of cerebrospinal fluid (CSF) cytokine levels. In addition, 15 healthy control CSF samples were used. Significantly increased CSF levels of IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-10 were observed early during the stroke with a peak on day 2 for the proinflammatory cytokines IL-8 and GM-CSF, and on day 3 for the immunoregulatory cytokine IL-10. Patients with a brain infarct predominantly located in the white matter showed significantly higher levels of IL-8 in CSF than patients with an infarct mainly located in the grey matter. Also, high levels of intrathecal tumour necrosis factor-alpha (TNF-alpha) were associated with the presence of white matter disease. Our study demonstrates an intrathecal production of proinflammatory and immunoregulatory cytokines in patients with stroke, supporting the notion of localized immune response to the acute brain lesion. A better understanding of the inflammatory response in stroke may lead to new treatment strategies.     

Increased in vitro induced CD4+ and CD8+ T cell IFN-gamma and CD4+ T cell IL-10 production in stable relapsing multiple sclerosis

Multiple sclerosis (MS) is presumed to be a T-cell mediated chronic inflammatory disease of the central nervous system. Investigators previously demonstrated increased IFN-gamma (pro-inflammatory) and IL-10 (counterregulatory anti-inflammatory) in MS. The balance of pro-inflammatory and counterregulatory anti-inflammatory cytokines may be important in the stabilization of disease activity. Purified CD4+ and CD8+ T cells from patients with clinically definite, stable relapsing MS (RRMS) were stimulated by anti-CD3 mAb or Con A for 48 hours and cytokine supernatants analysed for production of IL-2, IL-6, IFN-gamma, TNF-alpha (potential pro-inflammatory) and IL-4, IL-10, and TGF-beta (potential counterregulatory anti-inflammatory). Con A activated CD4+ and CD8+ T cell proinflammatory cytokine IL-2 secretion, CD4+ T cell IL-6 secretion, CD4+ and CD8+ T cell TNF-alpha secretion and CD8+ T cell IFN-gamma secretion was decreased significantly in RRMS subjects compared to controls. CD3 activated CD4+ and CD8+ T cell IL-6 secretion and CD4+ T cell TNF-alpha secretion was significantly decreased in MS subjects compared to controls. In contrast, there was increased CD3-induced IFN-gamma in both CD4+ and CD8+ T cells and counterregulatory anti-inflammatory CD3-induced IL-10 secretion in CD4+ T cells in RRMS compared to controls. These data suggest that an equilibrium of a pro-inflammatory (IFN-gamma) and a counterregulatory anti-inflammatory (IL-10) cytokine may define stable clinically definite early RRMS.     

IL-13 protects mice from lipopolysaccharide-induced lethal endotoxemia: correlation with down-modulation of TNF-alpha, IFN-gamma, and IL-12 production

IL-13 is a potent down-modulator of macrophage proinflammatory activity in vitro, similar in this context to the anti-inflammatory cytokines IL-4 and IL-10. Since IL-10 effectively confers protection to mice from LPS-induced lethal endotoxemia through inhibition of proinflammatory cytokine production, we investigated whether IL-13 may also be capable of providing protection in this experimental model of endotoxic shock. A single injection of recombinant murine IL-13 (rmIL-13; 0.5-10 microg) significantly increased survival in a dose-dependent manner when a lethal i.p. injection of endotoxin was administered to BALB/c mice. This effect appeared to be IL-13 specific, since survival was not affected in mice that received heat-inactivated rmIL-13. rmIL-13 provided significant protection to mice even when given 30 min after LPS injection; however, this protection decreased in a time-dependent manner as the administration of rmIL-13 was delayed by 1, 2, and 5 h following LPS injection. The protective effect of IL-13 was correlated with significant decreases in the production of the inflammatory mediators TNF-alpha, IFN-gamma, and IL-12 as well as a decrease in the anti-inflammatory mediator IL-10. Our data suggest that IL-13 provides protection from LPS-induced lethal endotoxemia in a manner that is similar to but independent from that of IL-10, and therefore can be added to the list of cytokine immunomodulators that might be beneficial in the treatment of septic shock.     

Interleukin-4 but not interleukin-10 inhibits the production of leukemia inhibitory factor by rheumatoid synovium and synoviocytes

The expression of the proinflammatory cytokine leukemia inhibitory factor (LIF) has been reported in the cartilage and synovium of rheumatoid arthritis (RA) patients. Here, we show that high levels of LIF were constitutively produced by cultures of synovium pieces. Low levels of LIF were produced spontaneously by isolated synoviocytes, but interleukin (IL)-1 beta caused a fourfold enhancement of this secretion. The anti-inflammatory cytokine IL-4 reduced the production of LIF by synovium pieces by 75%, as observed earlier with IL-6, IL-1 beta and tumor necrosis factor (TNF)-alpha. IL-4 had a direct effect since it inhibited LIF production by unstimulated and IL-1 beta- or TNF-alpha-stimulated synoviocytes. Conversely, IL-4 enhanced the production of IL-6, which shares with LIF biological activities and receptor components. The inhibitory effect of IL-4 was dose dependent and was reversed using a blocking anti-IL-4 receptor antibody. Similar inhibitory action of IL-4 on LIF production was observed on synovium pieces from patients with osteoarthritis and on normal synoviocytes. IL-10, another anti-inflammatory cytokine acting on monocytes, had no effect on LIF production by either synovium pieces or isolated synoviocytes. Thus, the production of LIF by synovium tissue was inhibited by IL-4 through both a direct effect on synoviocytes and an indirect effect by inhibition of the production of LIF-inducing cytokines.     

Resistance to lipopolysaccharide mediated by the Yersinia pestis V antigen-polyhistidine fusion peptide: amplification of interleukin-10

We previously showed that injection of homogenous staphylococcal protein A-V antigen fusion peptide into mice delayed allograft rejection and suppressed the major proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma) associated with generation of protective granulomas. This study was undertaken to determine if V antigen could prevent endotoxic shock, known to be mediated by excessive production of certain proinflammatory cytokines. After treatment with 50 microg of homogeneous V antigen-polyhistidine fusion peptide (Vh), the 50% lethal dose of purified lipopolysaccharide (LPS) in BALB/c mice immediately rose from 63 microg (normal controls) to 318 microg, fell to near baseline (71 microg) in 6 h, and then slowly rose to a maximum of 566 microg at 48 h before again returning to normal. Injected Vh alone (50 microg) promptly induced the anti-inflammatory cytokine interleukin-10 (IL-10) as well as modest levels of TNF-alpha (an inducer of IL-10) in spleen. Concomitant injection of Vh and an otherwise lethal dose of LPS (200 microg) dramatically decreased levels of TNF-alpha and IFN-gamma in the spleen and peritoneal lavage fluid as compared to values determined for LPS alone. These results would be expected if V antigen directly up-regulated IL-10 that is reported to generally down-regulate proinflammatory cytokines. Mice receiving 200 microg of LPS 48 h after injection of Vh exhibited patterns of cytokine synthesis similar to those observed in endotoxin-tolerant mice, a condition also reported to be mediated by IL-10. These findings suggest that V antigen serves as a virulence factor by amplifying IL-10, thereby repressing proinflammatory cytokines required for expression of cell-mediated immunity.     

Cytokines in rheumatoid arthritis. Potential targets for pharmacological intervention

The ingress of inflammatory leucocytes into the synovium is a crucial step in the pathogenesis of rheumatoid arthritis (RA). Cytokines are mediators involved in the inflammatory events, adhesive mechanisms, angiogenesis and osteopenia associated with RA. Pro- and anti-inflammatory cytokines, growth factors and chemokines all have an important role in these processes. Because the efficacy of currently used antirheumatic therapy is often limited, there is a need for more specific intervention strategies. Anticytokine therapy may include the use of monoclonal antibodies, antagonistic cytokines, soluble cytokine receptors, cytokine receptor antagonists, somatic gene transfer or other approaches. Hopefully, the study of cytokines and their interactions will lead to the development of new immunomodulatory strategies that will benefit patients with RA.     

Cytokine actions in the central nervous system

Cytokines and chemokines have been implicated in contributing to the initiation, propagation and regulation of immune and inflammatory responses. Also, these soluble mediators have important roles in contributing to a wide array of neurological diseases such as multiple sclerosis, AIDS Dementia Complex, stroke and Alzheimer's disease. Cytokines and chemokines are synthesized within the central nervous system by glial cells and neurons, and have modulatory functions on these same cells via interactions with specific cell-surface receptors. In this article, I will discuss the ability of glial cells and neurons to both respond to, and synthesize, a variety of cytokines. The emphasize will be on three select cytokines; interferon-gamma (IFN-gamma), a cytokine with predominantly proinflammatory effects; interleukin-6 (IL-6), a cytokine with both pro- and anti-inflammatory properties; and transforming growth factor-beta (TGF-beta), a cytokine with predominantly immunosuppressive actions. The significance of these cytokines to neurological diseases with an immunological component will be discussed.     

Cytokine regulation of human microglial cell IL-8 production

IL-8 involvement in neutrophil activation and chemotaxis may be important in inflammatory responses within the central nervous system, secondary to meningitis, encephalitis, and traumatic injury. The source of IL-8 within the brain during these inflammatory processes, however, is unknown. To explore the role of microglia in the production of IL-8, human fetal microglia, which are the resident macrophages of the brain, were treated with LPS and pro- and anti-inflammatory cytokines to determine their effects on IL-8 production. We found that IL-8 protein levels increased in response to LPS or IL-1 beta, or to TNF-alpha, which also corresponded to elevated IL-8 mRNA levels by RT-PCR. Pretreatment with IL-4, IL-10, or TGF-beta 1 potently inhibited the stimulatory effects of these proinflammatory agents. These findings indicate that human microglia synthesize IL-8 in response to proinflammatory stimuli, and that anti-inflammatory cytokines down-regulate the production of this chemokine. These results may have important therapeutic implications for certain central nervous system insults involving inflammation.     

Cytokines induce airway smooth muscle cell hyperresponsiveness to contractile agonists

Inflammatory cytokines have been shown to play an important role in the pathogenesis of various inflammatory processes. In throat infections, intracellular inflammatory cytokines have been detected from the sites of inflammation. The present study aimed to evaluate serum cytokine levels of patients with throat infections and correlate them to the inflammatory parameters and type of inflammation. Significantly higher inflammatory cytokine levels (interleukin [IL]-6 > 7 pg/mL, IL-1 > 1 beta pg/mL, tumor necrosis factor alpha > 1 pg/mL) were detected in most of the patients as opposed to healthy controls. Clinical parameters of infection (fever > 38 degrees C, leukocytosis > 11,000 white blood cells per cubic millimeter, polymorphonuclear neutrophils > 75%) were significantly correlated with high levels of inflammatory cytokines: mainly IL-6 and tumor necrosis factor alpha, and to a lesser degree with IL-1 beta. No correlation, however, was found between the type of inflammation and cytokine levels. The present study indicates a role of inflammatory cytokines in the pathogenesis of throat infections and the need for an anti-inflammatory and anticytokine therapeutic approach.     

The effect of azelastine on bronchial mucosa in bronchial asthma--suppression of cytokine mRNA

Azelastine is an oral antiallergic drug. Although oral antiallergic drugs are classified as controllers because of the possession of anti-inflammatory effect, the mechanism of action has remained obscure. Thus the author investigated the effects of azelastine on inflammatory cells infiltrating into the bronchial mucosa and on the expression of cytokines in patients with atopic asthma. Biopsy specimens of the bronchial mucosa were bronchoscopically obtained before and after the administration of azelastine for 3 months. Inflammatory cells in the bronchial mucosa, including eosinophils, mast cells, macrophages, and T lymphocytes, were stained immunocytochemistry; expression of cytokine mRNA [Interleukin (IL)-4 and IL-5] was examined by the in situ hybridization method. The results obtained revealed that the number of eosinophils (p < 0.01), T lymphocytes (p < 0.01), and cells expressing mRNA of IL-4 (p < 0.05) or IL-5 (p < 0.01) significantly decreased after the administration of azelastine. These results suggest that azelastine inhibits the action on local infiltration of inflammatory cells and following proinflammatory cytokine production as one mechanism of bronchial asthma.     

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.     

Staphylococcus aureus-induced septic arthritis and septic death is decreased in IL-4-deficient mice: role of IL-4 as promoter for bacterial growth

Lack of IL-4 has been shown to be protective in some experimental models of infectious diseases in mice such as cutaneous leishmaniasis. At the same time IL-4, together with other Th2 cytokines, including IL-10 and IL-13, is known as an anti-inflammatory cytokine with the potential to down-regulate proinflammatory cytokine production. To investigate the role of IL-4 in experimental Staphylococcus aureus-induced and T lymphocyte-mediated arthritis, IL-4-deficient C57BL/6 mice (IL-4(-/-)) and their congenic controls (IL-4(+/+)) were inoculated with a toxic shock syndrome toxin-1-producing S. aureus strain. In IL-4(+/+) mice, arthritis peaked 14 days after bacterial inoculation, whereas, at that time, IL-4(-/-) mice displayed significantly less frequent (p < 0.05) joint inflammation. Paralleling lower frequency of arthritis, IL-4-deficient mice showed a decreased bacterial burden in joints (p = 0.014) and kidneys (p = 0.029), as well as lower infection-triggered weight decrease and mortality. In vitro, IL-4 inhibited intracellular killing of S. aureus in infected macrophages, without affecting phagocytosis. This finding may explain the enhanced staphylococcal clearance observed in IL-4(-/-) mice in vivo. Our results suggest that IL-4 and IL-4-dependent Th2 responses promote septic arthritis and sepsis-related mortality by inhibition of bacterial clearance during S. aureus infection.     

Local cytokine response in Helicobacter pylori-infected subjects

The host immune response to Helicobacter pylori infection might be of importance with regard to the outcome of infection by this organism, e.g., to explain why only a proportion of infected subjects develop peptic ulcers. In this study we have analyzed the local response of different cytokines-i.e., the proinflammatory interleukin-1beta, (IL-1beta), IL-6, tumor necrosis factor alpha, and IL-8; the immunoregulatory gamma interferon (IFN-gamma); and IL-4; and the anti-inflammatory transforming growth factor beta (TGF-beta)-in antral biopsy specimens from H. pylori-infected duodenal ulcer (DU) patients and asymptomatic (AS) carriers (i.e., with chronic gastritis only). For comparison, biopsy specimens from uninfected healthy individuals were also analyzed. An immunohistochemical technique was used to allow quantification of the cytokine responses as well as identification of the cell types associated with the cytokine expression. We found that the levels of all of the studied cytokines except IL-4 were increased in the H. pylori-infected subjects compared to the levels in the healthy individuals. Our results indicate that the antral cytokine response is of the Th1 type since IFN-gamma, but not IL-4, was up-regulated both in H. pylori-infected DU patients and in AS carriers. However, there were no significant differences in either proinflammatory or immunoregulatory cytokine levels when H. pylori-infected subjects with and without peptic ulcers were compared. Some of the cytokines, particularly IL-1beta and TGF-beta, were also found in the gastric mucosae of healthy, uninfected subjects. We also showed that the gastric epithelium contributes substantially to the antral cytokine response of the proinflammatory cytokines IL-1beta and IL-6 in addition to IL-8.