Measuring T cell cytokines in allergic upper and lower airway inflammation: can we move to the clinic?

Recent insights regarding the development of allergic diseases such as allergic rhinitis, asthma and atopic eczema are based on the functional diversity of T helper (Th)1 and Th2 lymphocytes. Th2 cells (secreting Interleukin (IL)-4, IL-5, IL-9 and IL-13) are considered to be responsible for the induction and for many of the manifestations of atopic diseases. Local overproduction of Th2 cytokines at the site of allergic inflammation, and an intrinsic defect in the production of IFN-gamma by Th1 cells in atopic individuals, have now been reported by several authors. Both IFN-gamma and IL-10 have been suggested to play a modulatory role in the induction and maintenance of allergen-specific tolerance in healthy individuals. However, recent studies indicate that Th1 cells, secreting IFN-gamma might cause severe airway inflammation. On the other hand, 'inflammatory T cells' or Th17 cells, producing IL-17, could represent a link between T cell inflammation and granulocytic influx as observed in allergic airway inflammation. We focus in this review on local (at the side of inflammation) T cell cytokine production and cytokine production by circulating T cells (after in vitro restimulation) from individuals with allergic airway disease, rhinitis and/or asthma. We furthermore review the changes in local T cell cytokine production and/or cytokine production by circulating T cells (after restimulation in vitro) from allergic/asthmatic individuals after treatment with anti-inflammatory agents or immunotherapy. Finally, we discuss whether measuring these T cell cytokines in the airways might be of diagnostic importance or could help to follow-up patients with allergy/asthma.     

Moclobemide exerts anti-inflammatory effect in lipopolysaccharide-activated primary mixed glial cell culture

An increasing body of evidence indicates that glial activation and neuroinflammation play an important role in the pathogenesis of psychiatric and neurodegenerative diseases. Activated glial cells secrete various cytokines that influence neurotransmission, hypothalamus–pituitary–adrenal axis activity, neuronal plasticity and neurogenesis. It has been suggested that alterations in cytokine networks are involved in the mechanism of action of antidepressant drugs. Until now, only a few studies demonstrated that some tricyclic antidepressants and selective serotonin reuptake inhibitors reduced production of pro-inflammatory cytokines in brain glia cells. We have investigated for the first time whether the antidepressant, moclobemide (a reversible selective inhibitor of monoamine oxidase-A) has an influence on pro-inflammatory cytokines [interleukin (IL)-1β and tumor necrosis factor (TNF)-α] and anti-inflammatory cytokine (IL-10) in primary rat mixed glial cell cultures stimulated by lipopolysaccharide (LPS). Our results showed that moclobemide used in a wide range of concentrations diminished LPS-stimulated IL-1β and TNF-α mRNAs expression in cellular extracts and remarkably reduced the levels of both pro-inflammatory cytokines in culture medium. In opposite to this, the drug had no influence on IL-10 mRNA and slightly reduced IL-10 concentration. Moreover, moclobemide decreased LPS-stimulated translocation of NFκB p65 subunit into cellular nuclei. These results suggest that moclobemide exerts anti-inflammatory effect in the central nervous system because it affects the balance between pro- and anti-inflammatory cytokines (IL-1β, TNF-α/IL-10) in primary mixed glial cell cultures.     

Role of inflammatory mediators in angiogenesis

The angiogenic process involves several cell types and mediators, which interact to establish a specific microenvironment suitable for the formation of new capillaries from pre-existing vessels. Angiogenesis occurs in several physiological and pathological conditions, such as embryo development and wound healing, diabetic retinopathy and tumours. Inflammatory cells, namely monocytes/macrophages, T lymphocytes and neutrophils, fully participate in the angiogenic process by secreting cytokines that may affect endothelial cell (EC) functions, including EC proliferation, migration and activation. Angiogenesis is the result of a net balance between the activities exerted by positive and negative regulators. With regards to inflammatory cells and endothelium cross-talk, such balance is conceptually very similar to that of pro-inflammatory and anti-inflammatory mediators that modulate an appropriate inflammatory response. In this review we will mainly discuss the relevance of both physiological and pathological inflammatory processes in angiogenesis, with particular regards to microenvironmental contribution. We will also describe some of the most relevant pro-inflammatory cytokines in the modulation of the angiogenic process. Furthermore, we will concentrate on what has been recently reported about the mechanism by which some of these cytokines are induced during inflammation to promote a suitable microenvironment for angiogenesis and tumour progression. Pro-angiogenic cytokines, such as IL-1 and TNF, and anti-angiogenic cytokines such as IFN-gamma and IL-12, will be briefly described. We will try to provide a rationale for the use of both cytokines and cytokine blockades as novel potential pharmaceutical targets to modulate angiogenesis in chronic inflammation as well as in cancer.     

Adiponectin: a key fat-derived molecule regulating inflammation

Adiponectin is the abundant adipocyte-derived protein with well-established anti-atherogenic and insulin-sensitising properties. Besides these well characterised biological functions, recent evidence supports a strong anti-inflammatory function. Whereas initial studies demonstrated that adiponectin suppresses the production of the potent pro-inflammatory cytokine TNF-alpha, current studies showed that this adipokine also induces various anti-inflammatory cytokines, such as IL-10 or -1 receptor antagonists. These effects are paralleled by various other immune-regulatory properties, such as specific effects on endothelial cell functions. These in vitro effects are directly translated into various animal models of inflammation, demonstrating a potent anti-inflammatory effect for adiponectin. Thiazolidinediones selectively upregulate peroxisome-proliferator-activated receptor-gamma, leading to increased tissue and serum concentrations of adiponectin. Adiponectin has emerged as a key mediator regulating and affecting the balance between fat and inflammation. Therefore, either adiponectin itself or its inducing agents, such as thiazolidinediones, might be of key therapeutic interest in the near future far beyond diseases being associated with insulin resistance.     

Co-administration of a probiotic strain Lactobacillus plantarum LS/07 CCM7766 with prebiotic inulin alleviates the intestinal inflammation in rats exposed to N,N-dimethylhydrazine

The aim of this study was to determine the anti-inflammatory effects of preventive administration of a probiotic strain Lactobacillus plantarum LS/07 CCM7766 alone or in combination with prebiotic inulin or with flax-seed oil in the gut of rats, which developed chronic inflammation following administration of the pro-carcinogen N,N-dimethylhydrazine (DMH). After 28 weeks administration of probiotic/prebiotic-containing diet, rats were killed and their colons were examined by immunohistological criteria, whereas cytokines were determined in the jejunal mucosa. Application of DMH triggered the production of pro-inflammatory cytokines IL-2, IL-6, IL-17, and TNF-α, expression of pro-inflammatory mediators NF-κB, COX-2 and iNOS and caused depletion of goblet cells. Supplementing the diet with L. plantarum and its combination with the prebiotic abolished DMH-induced inflammatory process in the jejunal mucosa by inhibiting the production of pro-inflammatory cytokines and by stimulation of anti-inflammatory IL-10 cytokine synthesis, whereas concentration of TGF-β1 was not influenced significantly. Diet prevented a decrease in goblet cell numbers but numbers of mast cells were lowered only moderately. However, combined treatment of rats with L. plantarum and flax-seed oil had no significant effect on the parameters examined, except for decreased expression of NF-κB, in comparison with the negative control. Results indicate that the preventive administration of probiotic L. plantarum LS/07 CCM7766 alone or in combination with prebiotic inulin to rats with DMH-induced chronic inflammation can reduce inflammatory process in the jejunal and colon mucosa, probably indirectly, and involves down-regulation of synthesis of pro-inflammatory cytokines and suppression of NF-κB activity in mucosal cells.     

Anti-inflammatory and anti-apoptotic effects of strawberry and mulberry fruit polysaccharides on lipopolysaccharide-stimulated macrophages through modulating pro-/anti-inflammatory cytokines secretion and Bcl-2/Bak protein ratio

This study is the first to isolate strawberry (SP) and mulberry fruit polysaccharides (MP) and assess their anti-inflammatory and anti-apoptotic activities using lipopolysaccharide (LPS)-stimulated mouse primary macrophages. Pro-/anti-inflammatory cytokine levels secreted by LPS-stimulated macrophages cultured with SP and MP for 48 h were determined using ELISA method to evaluate anti-inflammatory effects of SP and MP. The Bcl-2/Bak (anti-/pro-apoptotic) protein levels in the cells were determined using Western blotting method to evaluate anti-apoptotic effects of SP and MP. The results showed that the maximum absorption peak of SP and MP appeared at 240 nm with a small shoulder around 280 ∼ 310 nm, suggesting that SP and MP might be glycoproteins. SP- and MP-treatment significantly (P < 0.05) decreased pro-inflammatory cytokines including interleukin (IL)-1β and IL-6, whereas the anti-inflammatory cytokine IL-10 was markedly increased, suggesting that SP and MP have anti-inflammation potential via modulating pro-/anti-inflammatory cytokine secretion profiles. Both SP and MP modulated Bak and Bcl-2 protein levels in the cells, suggesting that the SP and MP protected LPS-stimulated macrophages from apoptotic cell death. A negative correlation between cytokine secretion levels and Bcl-2 protein levels suggested that pro-inflammatory IL-1β and IL-6 cytokines decreased Bcl-2 levels in the LPS-stimulated macrophages.     

IL-10 plays a pivotal role in anti-inflammatory effects of resveratrol in activated microglia cells

The development of agents that can modulate microglial activation has been suggested as one potential strategy for the treatment or prevention of neurodegenerative diseases. Among these agents, resveratrol, with its anti-inflammatory action, has been described to have neuroprotective effects. In this paper we demonstrate that in LPS-stimulated microglia resveratrol pretreatment reduced, in a dose-dependent manner, pro-inflammatory cytokines IL-1β, TNF-α and IL-6 mRNA expression and increased the release of anti-inflammatory interleukin (IL)-10. Moreover, resveratrol pretreatment up-regulated the phosphorylated forms of JAK1 and STAT3, as well as suppressor of cytokine signaling (SOCS)3 protein expression in LPS activated cells, demonstrating that the JAK–STAT signaling pathway is involved in the anti-inflammatory effect exerted by resveratrol. By supplementing the cultures with an IL-10 neutralizing antibody (IL-10NA) we obtained the opposite effect. Taken together, these data allow us to conclude that the LPS-induced pro-inflammatory response in microglial cells can be markedly reduced by resveratrol, through IL-10 dependent up-regulation of SOCS3, requiring the JAK–STAT signaling pathway.     

Tumor necrosis factor-alpha monoclonal antibodies for Crohn's disease: tipping the balance

Crohn's disease (CD) is a chronic inflammatory disorder which may involve any part of gastrointestinal tract. Chronic inflammation is primarily due to an immunological imbalance between pro- and anti-inflammatory cytokines, and with a defective apoptosis of lamina propria T cells. Amongst the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) seems to play a central role in pathogenesis of CD. Over the last years, increasing knowledge on the pathogenesis of CD together with progresses in bio-technology have led to the development of a number of biological agents targeting specific molecules involved in gut inflammation, most importantly TNF-alpha and its receptors. The aim of this paper is to critically review the rationale and state-of-the art for the use TNF- alpha inhibitors in the treatment of CD.     

Role of cytokines in neurological disorders

The balance between cytokines with pro- and anti-inflammatory effects contributes to the course of the Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. TNFalpha seems to be an important factor in the cascade of events leading to demyelination and even axonal damage. During the acute phase, the serum concentrations of TNFalpha and IL-6 are elevated while anti-inflammatory cytokines are up-regulated in the recovery phase. Cytokines also have a key role in the pathogenesis of multiple sclerosis and most data suggest that this effect is mediated by myelin-specific CD4 T lymphocytes secreting Th type 1 cytokines. However, several different immune cells including B lymphocytes, CD8 T lymphocytes and NK T lymphocytes are also involved in the pathogenesis. Both Th1 and Th2 lymphocytes and cytokines probably participate in the development of myasthenia gravis (MG). The IFNalpha production is probably related to the severity of the disease, with clinical improvement associated with decreased production. The serum levels of IL-18 are significantly elevated in MG, with highest concentrations in patients with generalized disease. The immune system may be involved in the pathogenesis of AD by the effect of microglia, which can induce microglial activation with subsequent release of pro-inflammatory cytokines. In parkinsonism, there is evidence of chronic inflammation in the substantia nigra and striatum. Activated microglia, producing proinflammatory cytokines, surround the degenerating dopaminergic neurons and may contribute to the dopaminergic neuron loss. Studies of patients with epilepsy and animals with experimentally induced seizures indicate that cytokines may also influence the electrophysiological properties of neurons.     

Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response

Interleukin (IL)-10 performs an irreplaceable role in negatively regulating inflammation, primarily through a mechanism that selectively blocks the expression of pro-inflammatory genes encoding cytokines, chemokines, cell-surface molecules and other molecules involved in the propagation of inflammation. Not surprisingly, IL-10 has attracted interest as a tool to regulate inflammatory diseases. The clinical use of IL-10 as an anti-inflammatory agent has, however, not met expectations. Nevertheless, the signaling pathway used by the IL-10 receptor to generate the anti-inflammatory response is only beginning to be understood and could be a way to regulate inflammation by pharmacological agents.     

Cytokines: abnormalities in major depression and implications for pharmacological treatment

The role of cytokines in depression was first considered when the cytokine interferon resulted in "sickness behaviour", the symptoms of which are similar to those of major depression. The latter is associated with an increase in pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha). These cytokines are potent modulators of corticotropin-releasing hormone (CRH) which produces heightened hypothalamic-pituitary-adrenal axis (HPA) activity characterized by increases in ACTH and cortisol, both of which are reported elevated in major depression. Antidepressant treatment has immunomodulatory effects with increases in the production of IL-10, which is an anti-inflammatory cytokine. This review based on a Medline search from 1980-2003, focuses on the evidence available of cytokine changes in acute stress, chronic stress and major depression. It examines the effects of antidepressant treatment on immune parameters in both animal models and clinical trials. We suggest that future antidepressants may target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.     

Therapeutic benefits of regulating inflammation in autoimmunity

Autoimmunity results from the dysregulation of the immune system leading to tissue damage. Th1 and Th17 cells are known to be cellular mediators of inflammation in autoimmune diseases. The specific cytokine milieu within the site of inflammation or within secondary lymphatic tissues is important during the priming and effector phases of T cell response. In this review, we will address the nature of the inflammatory response in the context of autoimmune disease, specifically we will discuss the role of dendritic cells following stimulation of their innate pathogen recognition receptors in directing the development of T cell responses. We will focus on how dendritic cell subsets change the balance between major players in autoimmunity, namely Th1, Th17 and regulatory T cells. Th17 cells, once thought to only act as pathogenic effectors through production of IL-17, have been shown to have regulatory properties as well with co-production of the anti-inflammatory cytokine IL-10 by a subset now referred to as regulatory Th17 cells. IL-17 is important in the induction of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and inflammatory bowel disease (IBD). Study of the inflammatory process following encounter with agents that stimulate the innate immune responses such as adjuvants opens a new horizon for the discovery of therapeutic agents including those derived from microorganisms. Microbial products such as adjuvants that function as TLR ligands may stimulate the immune system by interacting with Toll-like receptors (TLR) on antigen-presenting cells. Microbial agents such as Bacille Calmette-Guérin (BCG) or Freund's adjuvant (CFA) that induce a Th17 response are protective in models of autoimmune diseases particularly EAE and type 1 diabetes (T1D). The induction of innate immunity by these microbial products alters the balance in the cytokine microenvironment and may be responsible for modulation of the inflammation and protection from autoimmunity.     

Anti-inflammatory properties of pro-inflammatory interferon-gamma

Production of interferon-gamma (IFNgamma) in response to infection is a hallmark of innate and adaptive immunity. In addition to the pivotal role of IFNgamma in host defense, its excessive release has been associated with the pathogenesis of chronic inflammatory and autoimmune diseases. In fact, knockout models reveal that IFNgamma plays a key role in mediating a number of pathological processes related to chronic immune activation. On the other hand, evidence has been accumulated in recent years that supports the concept of a dual role of IFNgamma in inflammation. Here, we review anti-inflammatory aspects of IFNgamma in the regulatory network of cytokine biology. These include induction of anti-inflammatory molecules such as interleukin (IL)-1 receptor antagonist (IL-1Ra) and IL-18 binding protein (IL-18BP), modulation of pro-inflammatory cytokine production, activation of apoptosis, and interference with the signal transduction machinery by induction of suppressors of cytokine signaling (SOCS).     

Immunomodulatory effects of azithromycin on the establishment of lipopolysaccharide tolerance in mice

Recent reports suggest that azithromycin can shift macrophage polarization towards the alternatively activated M2 phenotype. In order to investigate its immunomodulatory activity in vivo, the influence of azithromycin on survival and cytokine production was assessed in the LPS tolerance model which is characterized by an M2 skewed response. For induction of tolerance, mice received an intraplantar injection of 30 μg LPS, 24 h prior to intravenous challenge with 350 μg LPS. Azithromycin (100 mg/kg) was administered orally, 2 h before LPS application. Influence of treatment on survival and cytokine concentration in serum was monitored. Azithromycin alone, instead of LPS, could not induce an LPS tolerant state. However, when administered before LPS priming it significantly increased survival, which was enhanced by concomitant azithromycin before LPS challenge. Azithromycin had no effect on survival when administered only prior to the LPS challenge. Tolerance induction by LPS priming was associated, upon LPS challenge, with decreased serum concentrations of pro-inflammatory cytokines, TNFα, IL-12p40 and CCL5, and increased serum concentrations of the anti-inflammatory cytokines, IL-10 and IL-1ra. Azithromycin treatment, prior to LPS priming, further reduced serum TNFα and CCL5, yielding the greatest inhibition when the macrolide was also given prior to LPS challenge. Serum concentrations of the anti-inflammatory cytokines, IL-10 and IL-1ra, were unchanged following azithromycin treatment. In summary, we have confirmed the immunomodulatory activity of azithromycin, as reflected in its ability to augment tolerance induction to LPS, promoting increased survival and reduced pro-inflammatory cytokine production, without affecting overt inflammation to LPS or anti-inflammatory cytokine production.     

Statins as modulators of colon cancer cells induced cytokine secretion by human PBMC

The study was designed to examine whether the hydrophilic statin - pravastatin and the hydrophobic statin - simvastatin affect colon cancer cell-induced cytokine secretion by peripheral blood mononuclear cells (PBMC). Statins were added to human colon cancer cells (HT-29 and RKO), or to PBMC incubated separately or jointly. The secretion of the pro-inflammatory cytokines IL-1β and IFNγ and that of the anti-inflammatory cytokines IL-1ra and IL-10 induced by cancer cells was decreased by simvastatin but not by pravastatin, whereas that of IL-6 was not affected by both drugs. Conditioned media from colon cancer cells incubated with either simvastatin or pravastatin induced stimulation of cytokine production by PBMC similar to that caused by conditioned media derived from cancer cells incubated without the drugs, suggesting that simvastatin acts directly on the interaction between cancer and PBM cells. Simvastatin, but not pravastatin, caused inhibition of both cancer cell proliferation. The results imply that simvastatin may affect inflammation-induced colon cancer proliferation via alteration of the equilibrium between pro- and anti-inflammatory cytokines.     

IL-37 (IL-1F7) the newest anti-inflammatory cytokine which suppresses immune responses and inflammation

Cytokines such as interleukins, chemokines and interferons are immunomodulating and inflammatory agents, characterized by considerable redundancy, in that many cytokines appear to share similar functions. Virtually all nucleated cells, but especially epithelial cells and macrophages, are potent producers of cytokines. The objective of this study is to review the detailed mechanism of action and the biological profiles of IL-37, the newest anti-inflammatory cytokine. This review focuses on IL-37, a key cytokine in regulating inflammatory responses, mainly by inhibiting the expression, production and function of proinflammatory cytokines: IL-1 family pro-inflammatory effects are markedly suppressed by IL-37.     

Suppressive effect of TRH and imipramine on human interferon-gamma and interleukin-10 production in vitro

It has been established that thyrotropin-releasing hormone (TRH) affects several aspects of immunoreactivity, e.g. production of pro-inflammatory cytokines, and enhances therapeutic efficiency of classic tricyclic antidepressants. On the other hand, it has been suggested that pro-inflammatory cytokines play a role in the etiology of depression, whereas the therapeutic efficacy of antidepressants is related to their negative immunoregulatory effect. In order to verify the hypothesis that the TRH-induced increase in the therapeutic efficiency of classic tricyclic antidepressants results from synergistic inhibitory effects of those two agents on the secretion of pro-inflammatory cytokines, we studied the effect of imipramine appliedjointly with TRH on the production of IFN-gamma and IL-10 by human whole blood cells stimulated in vitro by mitogens. A significant decrease in the production of IFN-gamma and IL-10 cytokines, by 36% and 34%, respectively, was observed in cells stimulated with mitogens and co-incubated with imipramine and TRH (either given at a dose of 10(-5) M). Under the same conditions, TRH alone did not change the production of those cytokines. Furthermore, imipramine alone decreased, not statistically significantly, though, the production of IFN-gamma. Hence our data only partly support the above-mentioned hypothesis, since TRH and imipramine applied jointly suppress the production of both the pro-inflammatory IFN-gamma and the anti-inflammatory IL-10 cytokines.     

Emerging biotherapies for inflammatory bowel disease

The immunological and genetic pathogeneses of inflammatory bowel disease (IBD) have been well studied, but not well elucidated in recent years. Accordingly, the pharmacological treatment of IBD is focusing upon the individual pathologic step (targeting therapy). It has recently become apparent that new drugs such as biological immunomodulating agents and anti-inflammatory cytokines have better short-term effects in some respects than conventional drugs, and they could change the treatment strategy of IBDs in the near future. Many options are now available to treat IBD. The choice depends on the type of IBD, the location of inflammation and the severity of symptoms. Many key processes in the inflammatory cascade have been targeted by cytokine and anticytokine therapies ranging from antigen presentation, T cell activation, overproduction of pro-inflammatory cytokines and migration of inflammatory cells to blockade of effector signals. TNF-alpha plays an important role in the induction of other cytokines as well as in the upregulation of adhesion molecules in chronic IBDs, Crohn's disease (CD) and ulcerative colitis. In fact, the most successful approaches so far in the treatment of IBD have been anti-TNF strategies. In contrast, the use of antiadhesion molecules strategies has been demonstrated to be ineffective in IBD.     

Emerging biotherapies for inflammatory bowel disease

The immunological and genetic pathogeneses of inflammatory bowel disease (IBD) have been well studied, but not well elucidated in recent years. Accordingly, the pharmacological treatment of IBD is focusing upon the individual pathologic step (targeting therapy). It has recently become apparent that new drugs such as biological immunomodulating agents and anti-inflammatory cytokines have better short-term effects in some respects than conventional drugs, and they could change the treatment strategy of IBDs in the near future. Many options are now available to treat IBD. The choice depends on the type of IBD, the location of inflammation and the severity of symptoms. Many key processes in the inflammatory cascade have been targeted by cytokine and anticytokine therapies ranging from antigen presentation, T cell activation, overproduction of pro-inflammatory cytokines and migration of inflammatory cells to blockade of effector signals. TNF-α plays an important role in the induction of other cytokines as well as in the upregulation of adhesion molecules in chronic IBDs, Crohn’s disease (CD) and ulcerative colitis. In fact, the most successful approaches so far in the treatment of IBD have been anti-TNF strategies. In contrast, the use of antiadhesion molecules strategies has been demonstrated to be ineffective in IBD.