IL-1 family cytokines in inflammation and immunity

Emerging role of neuregulin-1beta1 in pathogenesis and progression of multiple sclerosis

Transient Pretreatment With Glucocorticoid Ablates Innate Toxicity of Systemically Delivered Adenoviral Vectors Without Reducing Efficacy

Toll-like Receptor 9 Triggers an Innate Immune Response to Helper-dependent Adenoviral Vectors

Interleukin 1 (IL-1) family is a group of cytokines with multiple local and systemic effects, which regulates both innate and adaptive immune responses. Generally, most IL-1 family cytokines express prevailing pro-inflammatory activities (IL-1α, IL-1β, IL-18, IL-33, IL-36 α, β, γ), whereas others are anti-inflammatory (IL-1Ra (IL-1 receptor antagonist), IL-36Ra, IL-38, IL-37). In addition to their immunomodulatory roles, some of them are also involved in the physiological modulation of homeostatic processes and directly affect mRNA transcription. IL-1 family cytokines bind to specific receptors composed of a ligand-binding chain and an accessory chain. The pro-inflammatory effects of IL-1 family cytokines are regulated on the level of transcription, enzymatic processing of precursors, release of soluble antagonists, and expression of decoy receptors. Members of the IL-1 family regulate the recruitment and activation of effector cells involved in innate and adaptive immunity, but they are also involved in the pathogenesis of chronic disorders, including inflammatory bowel disease, rheumatoid arthritis, and various autoimmune and autoinflammatory diseases. There are only limited data regarding the role of IL-1 cytokines in transplantation. In recent years, targeted therapeutics affecting IL-1 have been used in multiple clinical studies. In addition to the recombinant IL-1Ra, anakinra (highly effective in autoinflammatory diseases and tested for other chronic diseases), the monoclonal antibodies canakinumab, gevokizumab, and rilonacept (a long-acting IL-1 receptor fusion protein) provide further options to block IL-1 activity. Furthermore, new inhibitors of IL-18 (GSK 1070806, ABT-325, rIL-18BP (IL-18 binding protein)) and IL-33 (CNTO-7160) are presently under clinical studies and other molecules are being developed to target IL-1 family cytokines.

The p38 mitogen-activated protein kinase (MAPK) pathway, like the c-Jun N-terminal kinase (JNK) MAPK pathway, is activated in response to cellular stress and inflammation and is involved in many fundamental biological processes. To study the role of the p38 MAPK pathway in vivo, we have used homologous recombination in mice to inactivate the Mkk3 gene, one of the two specific MAPK kinases (MAPKKs) that activate p38 MAPK. Mkk3(-/-) mice were viable and fertile; however, they were defective in interleukin-12 (IL-12) production by macrophages and dendritic cells. Interferon-gamma production following immunization with protein antigens and in vitro differentiation of naive T cells is greatly reduced, suggesting an impaired type I cytokine immune response. The effect of the p38 MAPK pathway on IL-12 expression is at least partly transcriptional, since inhibition of this pathway blocks IL-12 p40 promoter activity in macrophage cell lines and IL-12 p40 mRNA is reduced in MKK3-deficient mice. We conclude that the p38 MAP kinase, activated through MKK3, is required for the production of inflammatory cytokines by both antigen-presenting cells and CD4(+) T cells.

Background:Mitochondrial function is implicated as a target of environmental toxicants and found in disease or injury models, contributing to acute and chronic inflammation. One mechanism by which mitochondrial damage can propagate inflammation is via activation of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, pyrin domain-containing receptor (NLRP)3 inflammasome, a protein complex that processes mature interleukin . plays an important role in the innate immune response and dysregulation is associated with autoinflammatory disorders.Objective:The objective was to evaluate whether mitochondrial toxicants recruit inflammasome activation and processing.Method:Murine macrophages (RAW 264.7) exposed to tri-organotins (triethyltin bromide (TETBr), trimethyltin hydroxide (TMTOH), triphenyltin hydroxide (TPTOH), bis(tributyltin)oxide) [Bis(TBT)Ox] were examined for pro-inflammatory cytokine induction. TMTOH and TETBr were examined in RAW 264.7 and bone marrow-derived macrophages for mitochondrial bioenergetics, reactive oxygen species (ROS) production, and inflammasome activation via visualization of aggregate formation, caspase-1 flow cytometry, enzyme-linked immunosorbent assay and Western blots, and microRNA (miRNA) and mRNA arrays.Results:TETBr and TMTOH induced inflammasome aggregate formation and release in lipopolysaccharide (LPS)-primed macrophages. Mitochondrial bioenergetics and mitochondrial ROS were suppressed. Il1a and Il1b induction with LPS or challenge was diminished. Differential miRNA and mRNA profiles were observed. Lower miR-151-3p targeted cyclic adenosine monophosphate (cAMP)-mediated and AMP-activated protein kinase signaling pathways; higher miR-6909-5p, miR-7044-5p, and miR-7686-5p targeted Wnt beta-catenin signaling, retinoic acid receptor activation, apoptosis, signal transducer and activator of transcription 3, IL-22, IL-12, and IL-10 signaling. Functional enrichment analysis identified apoptosis and cell survival canonical pathways.Conclusion:Select mitotoxic tri-organotins disrupted murine macrophage transcriptional response to LPS, yet triggered inflammasome activation. The differential response pattern suggested unique functional changes in the inflammatory response that may translate to suppressed host defense or prolong inflammation. We posit a framework to examine immune cell effects of environmental mitotoxic compounds for adverse health outcomes. https://doi.org/10.1289/EHP8314

The Interleukin-1 Family

Targeting Innate Immunity: A New Step in the Development of Combination Therapy for Chronic Hepatitis B

Rip2: a novel therapeutic target for bacteria-induced inflammation?

A DNA Microarray-based Analysis of the Host Response to a Nonviral Gene Carrier: A Strategy for Improving the Immune Response

The unrelenting bombardment by microbial pathogens from the environment and their increasing resistance to medical treatments are a constant threat to the survival of all organisms on earth. Microbes are covered by molecular patterns that are common among a broad range of pathogens. These include the lipopolysaccharides (LPS) of Gram-negative bacteria, lipoteichoic acids of Gram-positive bacteria, lipoproteins of bacteria and parasites, glycolipids of mycobacteria, mannans of yeast and double-stranded RNAs of viruses.1,2 Recognition of and responses to these molecules are controlled by a wide variety of cellular receptors. The best characterized receptors are the T-cell receptor and B-cell antibody receptor of the adaptive immune response, the specificity of which is randomly generated and clonally selected during the development of T and B lymphocytes.3 Unlike the receptors of the adaptive immune system, the pattern recognition receptors of the innate immune system have predetermined specificity generated early on in evolution and play an essential role in the determination of self versus non-self during the initial rapid responses to infection.1,2 As described in this review, a family of cell surface receptors, termed Toll-like receptors, are emerging as key regulators of host responses to infection.

Overview of the interleukin-1 family of ligands and receptors

“In this world there are only two tragedies. One is not getting what one wants, and the other is getting it.”—Oscar Wilde Tumor necrosis factor (TNF) has been referred to a “mixed blessing for higher organisms.”1 That is to say, although the controlled self-limited expression of TNF plays a critical role in activating host defense mechanisms and in homeostatic tissue repair, uncontrolled overexpression of TNF produces devastating consequences for the host organism, frequently leading to diffuse inflammation, multiorgan dysfunction, hemodynamic collapse, and death. Although a similar “bifunctional picture” for TNF has not yet emerged clearly for the heart, the report by Wada and colleagues2 in the present issue of Circulation suggests that TNF may be a mixed blessing for the heart as well. Several lines of evidence suggest that proinflammatory cytokines, such as TNF, play an important role in the pathogenesis of viral myocarditis. For example, elevated levels of TNF have been reported in patients with viral myocarditis.3 Importantly, TNF mRNA and protein are consistently upregulated in the hearts of patients with viral myocarditis.4 Mice with targeted overexpression of TNF in the cardiac compartment develop florid myocarditis and progressive myocardial fibrosis.5 6 The exogenous administration of TNF aggravates myocarditis, and the neutralization of TNF by antibodies or soluble receptors attenuates viral myocarditis.7 8 Taken together, these observations suggest that TNF plays an important pathophysiological role in the development and progression of viral myocarditis. In the present issue of Circulation , Wada and colleagues2 report that mice with targeted disruption of the TNF gene (TNF−/−) had increased mortality after infection with the encephalomyocarditis virus compared with wild-type mice (TNF+/+). Moreover, they showed that exogenous administration of TNF prevented the increase in virus–induced mortality in the TNF−/− mice. On the basis of …

Critical Role of VEGF-C/VEGFR-3 Signaling in Innate and Adaptive Immune Responses in Experimental Obliterative Bronchiolitis

Th2 Cytokine-Induced Alterations in Intestinal Smooth Muscle Function Depend on Alternatively Activated Macrophages