Cutting edge: is vasoactive intestinal peptide a type 2 cytokine?

A component of the chemical language shared by the immune and nervous system is the expression of neuropeptides by immune cells. Vasoactive intestinal peptide (VIP) was shown to be produced by T lymphocytes. Here we investigate whether T cell subsets differentially express VIP. Our studies indicate that, upon specific Ag stimulation, Th2 and T2 cells, but not Th1 and T1 cells derived from TCR transgenic (Tg) mice, express VIP mRNA and protein, and secrete VIP. Following immunization with the specific Ag, significant levels of VIP are present in the serum of syngeneic, non-Tg hosts that receive Th2, but not Th1 Tg cells. Th2 Tg cells recovered from the non-Tg hosts immunized with the specific Ag, but not with an irrelevant Ag, express intracellular VIP. Because VIP is produced by Ag-stimulated type 2 T cells, and differentially affects Th1 and Th2 cells, could VIP be viewed as a type 2 cytokine?     

Rap1 induces cytokine production in pro-inflammatory macrophages through NFκB signaling and is highly expressed in human atherosclerotic lesions

Repressor activator protein 1 (Rap1) is essential for maintaining telomere length and structural integrity, but it also exerts other non-telomeric functions. The present study tested the hypothesis that Rap1 is released into the cytoplasm and induces production of pro-inflammatory cytokines via nuclear factor kappa B (NFκB) signaling in macrophages, a cell type involved in the development and progression of atherosclerotic lesions. Western blotting analysis confirmed that Rap1 was present in the cytoplasm of differentiated human monocytic leukemia cells (THP-1, a macrophage-like cell line). Co-immunoprecipitation assay revealed a direct interaction between Rap1 and I kappa B kinase (IKK). Knockdown of Rap1 suppressed lipopolysaccharide-mediated activation of NFκB, and phosphorylation of inhibitor of kappa B α (IκBα) and p65 in THP-1 macrophages. The reduction of NFκB activity was paralleled by a decreased production of NFκB-dependent pro-inflammatory cytokines and an increased expression of IκBα (native NFκB inhibitor) in various macrophage models with pro-inflammatory phenotype, including THP-1, mouse peritoneal macrophages and bone marrow-derived M1 macrophages. These changes were observed selectively in pro-inflammatory macrophages but not in bone marrow-derived M2 macrophages (with an anti-inflammatory phenotype), mouse lung endothelial cells, human umbilical vein endothelial cells or human aortic smooth muscle cells. Immunostaining revealed that Rap1 was localized mainly in macrophage-rich areas in human atherosclerotic plaques and that the presence of Rap1 was positively correlated with the advancement of the disease process. In pro-inflammatory macrophages, Rap1 promotes cytokine production via NFκB activation favoring a pro-inflammatory environment which may contribute to the development and progression of atherosclerosis.     

Is interleukin-6 the necessary pyrogenic cytokine?

(1) This paper analyses arguments suggesting a critical role for interleukin-6 (IL-6) in the manifestation of fever.

(2) Evidence supporting such a role for IL-6 derives from the excellent correlation between IL-6 in plasma and the accompanying fever, from neutralization experiments with anti-IL-6-antibodies, and from studies in IL-6-deficient mice.

(3) Peripherally administered IL-6 has rather poor pyrogenic properties and needs co-factors to elicit pronounced fever.

(4) Circumventricular organs, which lack a tight blood–brain barrier, have been identified as brain sites where circulating IL-6 causes a direct genomic activation of cellular elements in astrocytes and endothelial cells.

(5) Due to the fact that the onset of fever frequently preceeds the formation of sufficient amounts of IL-6 and the activation of brain cells by this cytokine, it is suggested that IL-6 contributes to the maintenance rather than to the induction of the initial phase of fever.

(6) During the time course of fever IL-6 seems to be involved in the induction of endogenous anti-inflammatory/antipyretic mediators and thus in the manifestation of defervescence.     

Disturbance of cytokine networks in Sjögren's syndrome

The difficulty in predicting the consequences of interactions between different cytokine networks has increased with the expansion of the T helper (Th) cell universe and the discovery of numerous B lymphocyte-derived cytokines. Consequently, it is now difficult to conceptualize a straightforward view of the contribution of these disturbances to the pathogenesis of primary Sj?gren's syndrome (SS). Th1 cells, which produce interferon-γ and IL-2, and Th17 cells, which make IL-17 and TNF-α, have been cast in the leading roles of the play. However, the complex role of T-cell subsets in SS is accentuated by the reciprocal effects of Th17 cells and regulatory T cells found in salivary glands of SS patients. Furthermore, B lymphocyte polarization into type-1 B effector (Be1) and Be2 cells and B-cell modulating factors of the TNF family, most notably the B-cell-activating factor (BAFF), and their prominent role in SS are additional complicating factors. Whereas Th17 cells orchestrate autoreactive germinal centers, local BAFF would repress the generation of Th17 cells. Such new insights into interconnected cytokines in primary SS may lead to new treatments for these patients.     

Proinflammatory cytokine gene polymorphisms in Behçet's disease

Beh?et's disease (BD) is a chronic, systemic disease, characterized by oral and genital lesions, and ocular inflammation. There is evidence indicating altered levels of proinflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α) in patients with BD. This study involved 150 patients with BD and 140 healthy controls, and investigated the role of proinflammatory cytokine gene polymorphisms in the disease. The frequency of the TNF-α (-238) G/G genotype was significantly higher in the patient group, compared to the controls (p < 0.001), whilst the G/A genotype was significantly lower in the patients with BD (p < 0.001). Patients with BD showed a significant increase in the TNF-α (- 308, - 238) GG haplotype (p < 0.001), whilst there was a significant decrease in the GA haplotype (p < 0.001). The heterozygous, IL-6 (- 174) C/G genotype (p = 0.005), and the IL-6 (- 174, nt565) haplotype CG (p < 0.001), were significantly decreased in the patient group. The increased production of proinflammatory cytokines in BD could be a consequence of specific, cytokine gene polymorphisms. Particular genotypes and haplotypes in TNF-α were over-represented in BD, which may, in turn, predispose individuals to this disease.     

Langerhans cell histiocytosis: a cytokine/chemokine-mediated disorder?

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by an abnormal accumulation and/or proliferation of cells with a Langerhans cell phenotype. Although no clear cause of LCH has been identified, it has been postulated that LCH might be the consequence of an immune dysregulation, causing Langerhans cells to migrate to and accumulate at various sites. Production of cytokines and chemokines is a central feature of immune regulation. Cytokines are abundantly present within LCH lesions. We review here the potential role of cytokines and chemokines in the pathogenesis of LCH. The type, distribution, and number of different cytokines released within lesions can provide clues to the possible aetiology of LCH and, ultimately, might offer therapeutic possibilities using recombinant cytokines or antagonists for this disorder.     

Human leukocyte antigen and interleukin 2, 10 and 12p40 cytokine responses to measles: is there evidence of the HLA effect?

HLA class I and class II associations were examined in relation to measles virus-specific cytokine responses in 339 healthy children who had received two doses of live attenuated measles vaccine. Multivariate linear regression modeling analysis revealed suggestions of associations between the expression of DPA1*0201 (p=0.03) and DPA1*0202 (p=0.09) alleles and interleukin-2 (IL-2) cytokine production (global p-value 0.06). Importantly, cytokine production and DQB1 allele associations (global p-value 0.04) revealed that the alleles with the strongest association with IL-10 secretion were DQB1*0302 (p=0.02), DQB1*0303 (p=0.07) and DQB1*0502 (p=0.06). Measles-specific IL-10 secretion associations approached significance with DRB1 and DQA1 loci (both global p-values 0.08). Specifically, suggestive associations were found between DRB1*0701 (p=0.07), DRB1*1103 (p=0.06), DRB1*1302 (p=0.08), DRB1*1303 (p=0.06), DQA1*0101 (p=0.08), and DQA1*0201 (p=0.04) alleles and measles-induced IL-10 secretion. Further, suggestive association was observed between specific DQA1*0505 (p=0.002) alleles and measles-specific IL-12p40 secretion (global p-value 0.09) indicating that cytokine responses to measles antigens are predominantly influenced by HLA class II genes. We found no associations between any of the alleles of HLA A, B, and Cw loci and cytokine secretion. These novel findings suggest that HLA class II genes may influence the level of cytokine production in the adaptive immune responses to measles vaccine.     

Decidual natural-killer-cell interaction with trophoblast: cytolysis or cytokine production?

At the implantation site, the uterine mucosa (decidua) is infiltrated by large numbers of natural killer (NK) cells. These NK cells are in close contact with the invading fetal trophoblast and we have proposed that they might be the effector cells that control the implantation of the allogeneic placenta. Recent characterization of NK cell receptors and their HLA class I ligands has suggested potential mechanisms by which NK cells might interact with trophoblast. However, what happens as a result of this interaction is not clear. The traditional method for investigating NK cell function in vitro is the protection from lysis of target cells by expression of HLA class I antigens. This might not be an accurate reflection of what happens in vivo. Another function of NK cells is the production of cytokines on contact with target cells. This could be an important outcome of the interaction between decidual NK cells and trophoblast. Decidual NK cells are known to produce a variety of cytokines; trophoblast cells express receptors for many of these cytokines, indicating that they can potentially respond. In this way, decidual NK cells have a significant influence on trophoblast behaviour during implantation.     

Can interleukin-10 be used as a true immunoregulatory cytokine?

Interleukin-10 (IL-10) is a cytokine that is currently regarded as a potential therapy for inflammatory diseases involving T helper 1-type responses because of its ability to downregulate several major functions of Th1 cells and macrophages. There are also evidence that IL-10 could be useful in controlling Th2-mediated inflammatory processes. However IL-10 has also immunostimulatory properties especially on B-cells and activated CD8+ T cells. These pleiotropic effects may explain the discrepancy observed after IL-10 treatment in different in vivo experimental models. We have recently shown that IL-10 induces the differentiation of a subset of regulatory CD4+ T cells (Tr1). In different in vivo models, these cells were shown to inhibit Th1 and Th2-type inflammatory responses through the secretion of IL-10. These Tr1 cells may thus be used in specific cellular therapy in order to deliver IL-10 precisely at the site of inflammation.     

Human macrophage migration inhibitory factor: a proven immunomodulatory cytokine?

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory mediator with the ability to induce various immunomodulatory responses and override glucocorticoid-driven immunosuppression. Some of these functions have been linked to the unusual enzymatic properties of the protein, namely tautomerase and oxidoreductase activities. However, there are conflicting reports regarding the functional role of these enzymatic properties in normal physiological homeostasis and disease progression. Therefore, we have produced a highly pure, virtually endotoxin-free recombinant MIF preparation and fully characterized this using a variety of biochemical and biophysical approaches. The recombinant protein, with demonstrable enzymatic activity, was then used to systematically examine the biological activity of MIF. Surprisingly, treatment with MIF alone failed to induce cytokine expression, with the exception of IL-8. However, co-treatment of lipopolysaccharide (LPS) in conjunction with MIF produced synergistic secretion of tumor necrosis factor-alpha, interleukin (IL)-1, and IL-8 compared with LPS alone. The potentiating effect of MIF was seen at physiologically relevant concentrations. These data suggest that MIF has no conventional cytokine activity but, rather, acts to modulate and amplify the response to LPS.     

Can cord blood cells support the cytokine storm in GvHD?

Cord blood has a high number of proliferating hematopoietic progenitors and is therefore used as an alternative source of hematopoietic cells for allogeneic transplantation. In addition there is a wider availability of cord blood and a lower cost of procurement compared to bone marrow. However one of the most interesting immunological benefits of a cord blood transplant that has been proposed is the low severity of Graft versus Host Disease (GvHD). This review aims to address some of the immunological reasons why this may be the case by assessing the role of cord blood cytokines in the cytokine storm of GvHD.     

Expression of cytokine mRNA during immuno—modulation of murine suppressor macrophages

In order to analyze the mechanism of immunomodulation by LPS on murine peritoneal suppressor macrophages,we have,using RNase protection assay,checked the changes of mRNA expression pattern of several cytokine genes during the immuno-modulation.It has been found that,after treating peritoneal suppressor macrophages with LPS,mRNAs of IL-12 p35,IL-12 p40,IL-6 and IFN-γ are newly appeared,while those of IL-1α,IL-1β and IL-1Ra are increaseb and those of other cytokines,like TGF-β1 and MIF are not changed at all.It seems certain that those cytokines,whose expression is increased by LPS stimulation,may be responsible for the functional changes of suppressor macrophages during immuno-modulation.Among these changes,the appearance of IL-12 mRNA may play a critical role,and,in this regard,the synergetic effect betewwn IFN-γ and LPS on the increase of IL-12 p35 and IL-12 p40 mRNA expression is an interesting finding.