Biologics targeting IL-5, IL-4 or IL-13 for the treatment of asthma – an update

Introduction: The development of monoclonal antibody-based biologics targeted at inhibition of the Th2 cytokines IL-4, IL-5 and IL-13 represent potentially effective treatments for patients with the glucocorticoid refractory eosinophilic asthma phenotype.

Areas covered: Asthma exhibits marked heterogeneity both clinically and at the molecular phenotypic level, requiring specifically targeted treatments to block the key pathways of the disease. It is becoming apparent that significant clinical effects with anti-cytokine-based biologic therapies are more likely in carefully selected patient populations that take asthma phenotypes into account. The development of reproducible and straightforward discriminatory biomarkers may aid identification of those patients most likely to benefit from treatment with these expensive interventions. This narrative review is based on English-language original articles in PubMed or Med-Line that reported significant clinical findings published in the last two years on the evidence demonstrating the effectiveness or otherwise of the targeting of IL-4, IL-5, or IL-13 in carefully selected patients with severe refractory asthma.

Expert commentary: The use of a baseline peripheral blood eosinophilia as a simple reproducible biomarker to identify patients with particular sub-phenotypes of asthma to guide the effective use of biologic therapy represents a significant step forward.     

The critical role of IL-12 and the IL-12Rβ2 subunit in the generation of pathogenic autoreactive Th1 cells

Experimental Allergic Encephalomyelitis (EAE) is a demyelinating disease of the central nervous system which is an animal model for the human autoimmune disease, multiple sclerosis. EAE is mediated by CD4⁺ T cells and the T cells responsible for disease induction produce Th1 cytokines. IL-12 produced by monocytes and dendritic cells is the most critical factor which influences the development and differentiation of pathogenic autoreactive Th1 cells. Here, we review our recent studies on the critical contributions of IL-12 and the IL-12Rβ2 subunit to the generation of autoreactive effector cells which mediate EAE. In addition, we discuss the potential contribution of IL-18 to the upregulation of the IL-12/IL-12Rβ2 pathway and the contribution of the suppressor cytokines, IL-4 and IL-10, in downregulating this pathway. Collectively, our studies demonstrate that the IL-12/IL-12Rβ2 pathway is a critical intermediary in the process of Th1 differentiation which can be both positively or negatively regulated. This pathway remains an attractive immunotherapeutic target for blockade of function with inhibitory reagents or downregulation by Th2 cytokines.     

IL-1β/IL-6 network in the tumor microenvironment of human colorectal cancer

Objectives

Recent studies suggest that the interaction between interleukin (IL)-1β and IL-6 in the microenvironment might be involved in the development and progression of human colorectal cancer (CRC). However, the expression of IL-1β/IL-6 network within the CRC microenvironment is not fully understood.

Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1

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Evaluation of the Influence of N-Nitrosodimethyloamine (NDMA) on the Apoptosis of Neutrophils of Peripheral Blood (PMN) and the Expression of the IL-6R Membrane Receptor—in vitro Research

Evaluation of the influence of N-nitrosodimethyloamine (NDMA) on the apoptosis of neutrophils of peripheral blood (PMN) and the expression of the IL-6R membrane receptor - in vitro research.

The aim of the present work was the evaluation of N-nitrosodimethyloamine (NDMA) on the induction of apoptosis in the neutrophils of peripheral blood as well as the evaluation of the surface receptors for IL-6. The isolated neutrophils were incubated for 1 and 3 hours with NDMA of a concentration of 2.5, 5, 7.5, and 10 mg/ml. In the samples incubated for 1 hour a significant, dose- dependent increase of apoptosis in the examined cells was observed. In the cells incubated for 3 hours, the increase of apoptosis was observed only at concentration of NDMA of 2.5 and 5 mg/ml. In case of higher concentration used, probably necrotic processes dominated in the cells. No influence of NDMA on the expression of IL-6R was observed.     

Serum levels of TGFβ, IL-10, IL-17, and IL-23 cytokines in β-thalassemia major patients: the impact of silymarin therapy

Several immunological abnormalities have been characterized in β-thalassemia, many of which are linked to or identified with cytokines. In this study, we investigated the serum levels of TGF-β, IL-10, IL-17 and IL-23 in β-thalassemia major patients in comparison with healthy controls. The immunomodulatory effect of silymarin (a flavonoid complex obtained from Silybum marinum) on the serum levels of cytokines was further evaluated in thalassemia patients receiving silymarin (420?mg/day) and compared with patients treated with placebo for 6-month. Serum cytokines levels were measured by enzyme linked immunosorbent assay (ELISA). The results showed a significant higher concentration of TGF-β and IL-23 in the patient group than control group. Among studied cytokines, a significant reduction in serum IL-10 levels was found in patients treated with silymarin when compared with IL-10 values at baseline. However, no significant difference was observed between baseline values of cytokine compared with end values in placebo group. Our data suggest the presence of imbalanced immune condition involving inflammation and immunosuppression in thalassemia patients, which could be modulated to a more effective immune response by silymarin.     

Association of IL-1β, IL-1Ra and FABP1 gene polymorphisms with the metabolic features of polycystic ovary syndrome

Background

Polycystic ovary syndrome (PCOS), a highly prevalent endocrinopathy is currently being designated as chronic low grade inflammatory state. IL-1β, IL-1Ra and FABP1 are critical mediators of inflammatory processes and are speculated to play a role in the pathogenesis of PCOS. The aim of this study was to study the association of IL-β, IL-1Ra and FABP1 gene polymorphisms with PCOS and related metabolic features.

Subjects

95 PCOS and 45 age matched healthy control subjects were enrolled in this study.

Methods

Polymorphism in genes IL-1β, IL-1Ra and FABP1 was studied by PCR, PCR–RFLP and sequencing methods, respectively. Hormonal and lipid profiles were evaluated for all the subjects.

Results

Hormonal and lipid profiles showed significant differences between PCOS and control subjects. Allele and genotype frequencies of IL-1β, IL-1Ra and FABP1 gene polymorphisms did not vary between the control and PCOS group. However, T allele of C[-511]T variant of IL-1β, allele II in intron 2 of IL-1Ra and A allele of A/G variant of FABP1 (rs2197076) showed significant association with many metabolic features associated with PCOS.

Conclusions

Polymorphism in genes encoding cytokines and proteins involved in lipid metabolism can provide insights into the genetics of the disease and may contribute to assess the associated risk of cardiovascular diseases (CVD), dyslipidemia and metabolic syndrome (MetS) associated with PCOS.

     

IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-γ are not

Psoriasis is a common chronic skin disease with a largely unknown pathogenesis. We demonstrate here that transgenic over-expression of interleukin (IL)-22 in mice resulted in neonatal mortality and psoriasis-like skin alterations including acanthosis and hypogranularity. This cutaneous phenotype may be caused by the direct influence of IL-22 on keratinocytes, since this cytokine did not affect skin fibroblasts, endothelial cells, melanocytes, or adipocytes. The comparison of cytokines with hypothesized roles in psoriasis pathogenesis determined that neither interferon (IFN)-γ nor IL-17, but only IL-22 and, with lower potency, IL-20 caused psoriasis-like morphological changes in a three-dimensional human epidermis model. These changes were associated with inhibited keratinocyte terminal differentiation and with STAT3 upregulation. The IL-22 effect on differentiation-regulating genes was STAT3-dependent. In contrast to IL-22 and IL-20, IFN-γ and IL-17 strongly induced T-cell and neutrophilic granulocyte-attracting chemokines, respectively. Tumor necrosis factor-α potently induced diverse chemokines and additionally enhanced the expression of IL-22 receptor pathway elements and amplified some IL-22 effects. This study suggests that different cytokines are players in the psoriasis pathogenesis although only the IL-10 family members IL-22 and IL-20 directly cause the characteristic epidermal alterations. Kerstin Wolk and Harald S. Haugen equally contributed to this work.     

An additional piece in the puzzle of neutrophil-derived IL-1β: the NLRP3 inflammasome

The notion that neutrophils play a pivotal role in orchestrating ongoing inflammatory immune responses has been bolstered by several fairly newly described effector mechanisms, particularly their capacity to serve as a source of cytokines. This frequently neglected phenomenon is acquiring more and more credit and, as a result, our understanding of the molecular basis of neutrophil-derived cytokines has grown tremendously in the past 20 years. It is now clear that cytokine secretion by neutrophils is controlled by sophisticated regulatory mechanisms. In this issue of the European Journal of Immunology, Mankan et al. (Eur. J. Immunol. 42: 710-715) further extend our knowledge by reappraising the role of the inflammasome pathway, specifically the NLRP3 sensor, in the secretion of mature IL-1β by murine neutrophils. Accordingly, Mankan et al. (Eur. J. Immunol. 42: 710-715) identify the neutrophil expression of the NLRP3 inflammasome complex, and by using specific knockout mice, they also show that, in LPS-primed neutrophils, the NLRP3/ASC/caspase-1 axis plays a nonredundant role for IL-1β processing in response to typical NLRP3 inflammasome stimuli.     

RORγt-dependent IL-17A-producing cells in the pathogenesis of intestinal inflammation

The hypothesis of helper T (T(h))1/T(h)2 cytokine balance proposed by Mosmann and Coffman is often invoked to explain the development of inflammatory diseases, including inflammatory bowel diseases (IBD). Recently, however, a newly identified class of T(h) cells-T(h)17 cells, which produce T(h)17 family cytokines-has been recognized as an essential subpopulation in the development of almost all kinds of human and animal inflammatory diseases, rather than T(h)1 and T(h)2 cells. A representative T(h)17 family cytokine, interleukin (IL)-17A, is produced by not only T(h)17 cells, but also by other types of cells, such as T-cell receptor γδ T cells, natural killer (NK) T cells, NK cells, myeloid cells, and innate lymphoid cells, which may also be critically involved in the initiation and persistence of IBD. Here we review recent advances in the study of such IL-17A-producing cells in the pathogenesis of IBD.     

Astrocytic growth through the autocrine/paracrine production of IL-1β in the early infectious phase of fowl glioma-inducing virus

Fowl glioma is characterized morphologically by multiple nodular astrocytic growth with disseminated non-suppurative encephalitis. The disease is caused by fowl glioma-inducing virus (FGV) and its variants, belonging to subgroup A of avian leukosis virus (ALV-A). Fifty-seven FGV variants have so far been isolated from Japanese fowls and these variants have a variable degree of glioma inducibility. However, how these ALVs induce glioma with different degrees and frequencies has not been fully elucidated. In this study, we investigated the relationship between intracerebral viral replication and astrocytic growth in the early infectious phase. Replication abilities of two ALV strains, Sp-53 (a FGV variant) and ALV-based replication-competent vector RCAS(A) without glioma inducibility, were compared in the brains of C/O specific pathogen free chickens at 35 days of age. Sp-53 replicated faster than RCAS(A), and the histological score and the level of interleukin (IL)-1β in brains increased depending on the level of intracerebral viral RNA. Up-regulation of IL-1β was also demonstrated in primary cultured astrocytes. These results suggest that the astrocytic growth in this phase is enhanced through the autocrine/paracrine production of IL-1β in the FGV-infected astrocytes.     

TGF-β limits IL-33 production and promotes the resolution of colitis through regulation of macrophage function

M?s promote tissue injury or repair depending on their activation status and the local cytokine milieu. It remains unclear whether the immunosuppressive effects of transforming growth factor β (TGF‐β) serve a nonredundant role in M? function in vivo. We generated M?‐specific transgenic mice that express a truncated TGF‐β receptor II under control of the CD68 promoter (CD68TGF‐βDNRII) and subjected these mice to the dextran sodium sulfate (DSS) model of colitis. CD68TGF‐βDNRII mice have an impaired ability to resolve colitic inflammation as demonstrated by increased lethality, granulocytic inflammation, and delayed goblet cell regeneration compared with transgene negative littermates. CD68TGF‐βDNRII mice produce significantly less IL‐10, but have increased levels of IgE and numbers of IL‐33⁺ M?s than controls. These data are consistent with associations between ulcerative colitis and increased IL‐33 production in humans and suggest that TGF‐β may promote the suppression of intestinal inflammation, at least in part, through direct effects on M? function.     

Modulation of the Functions of Dengue Virus-Specific Human CD8+ Cytotoxic T Cell Clone by IL-2, IL-7 and IFNγ

Lymphokines play an important role in immune responses to viruses by modulating functions of T lymphocytes. In the present study, we examined the effects of interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-7 (IL-7), and interferon gamma (IFNγ) on proliferation, cytotoxic activity and lymphokine production of a dengue virus-specific CD8⁺ human cytotoxic T lymphocyte (CTL) clone. IL-2 and IL-7 induced proliferation of the CD8+ CTL clone in the presence or absence of specific antigen, while IFNγ suppressed proliferation of the clone. IL-7 and IFNγ augmented dengue virus-specific cytotoxic activity without inducing non-specific cytotoxic activity, and IL-2 induced non-specific cytotoxic activity. IL-2 induced IFNγ production by the CD8+ CTL clone. IL-4 and IL-6 did not modulate the functions of the CD8+ CTL clone in these experimental conditions.

These results suggest that functions of dengue virus-specific CD8+ CTL are modulated by IL-2, IL-7 and IFNγ, and that IL-7 is a lymphokine useful to induce growth and to maintain specific cytotoxic activity of CD8+ CTL clones in vitro.     

Uric acid induces trophoblast IL-1β production via the inflammasome: implications for the pathogenesis of preeclampsia

Citation
Mulla MJ, Myrtolli K, Potter J, Boeras C, Kavathas PB, Sfakianaki AK, Tadesse S, Norwitz ER, Guller S, Abrahams VM. Uric acid induces trophoblast IL‐1β production via the inflammasome: implications for the pathogenesis of preeclampsia. Am J Reprod Immunol 2010; 65: 542–548 Problem  Preeclampsia is associated with hyperuricemia, which correlates with the disease severity. Levels of circulating uric acid increase before the clinical manifestations, suggesting that they may be causally related. Uric acid, or monosodium urate (MSU), activates the Nod‐like receptor, Nalp3, leading to inflammasome activation and IL‐1β processing. Because preeclampsia is associated with placental immune/inflammatory dysregulation, we sought to determine in the trophoblast, the presence of the Nalp3 inflammasome, and the effect of MSU on its activation. Method of study  Isolated first‐ and third‐trimester trophoblasts were assessed for expression of the inflammasome components, Nalp1, Nalp3, and ASC. First‐trimester trophoblast cells were incubated with or without MSU, and after which, IL‐1β secretion and processing and caspase‐1 activation were determined. Results  Trophoblast cells expressed Nalp1, Nalp3, and ASC under basal conditions. Following incubation with MSU, first‐trimester trophoblast IL‐1β secretion was upregulated. This correlated with increased expression levels of active IL‐1β and active caspase‐1. ASC knockdown reduced MSU‐induced IL‐1β secretion. Conclusion  These findings demonstrate that uric acid activates the inflammasome in the trophoblast, leading to IL‐1β production. This may provide a novel mechanism for the induction of inflammation at the maternal–fetal interface leading to placental dysfunction and adverse pregnancy outcome, including preeclampsia.