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Phosphodiesterases
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Moritz Helmstädter, Manfred Schubert-Zsilavecz
It was noticed that PDE4 isoforms have a high level of expression in cells that regulate inflammatory responses and tissue remodelling such as most immune cells including macrophages, neutrophils, eosinophils and lymphocytes (Torphy, 1998; Korhonen et al., 2013). Early PDE4-selective inhibitors such as rolipram showed potent cAMP-mediated anti-inflammatory effects both in cellular and animal models which motivated pharmaceutical companies to invest a lot in developing PDE inhibitors for inflammation-related diseases such as asthma, COPD, allergic rhinitis and idiopathic pulmonary fibrosis. Experiments with carrageenan-induced paw inflammations show that rolipram increases the expression of mitogen-activated protein kinase phosphatase 1 (MKP-1). Additionally PDE4-Inhibitors suppress a variety of inflammatory responses including proliferation, chemotaxis, phagocytosis and release of pro-inflammatory mediators (Raker et al., 2016). Increased intracellular cAMP attenuates the expression of pro-inflammatory cytokines such as tumour necrosis factor alpha and leads to a higher production of anti-inflammatory cytokines such as interleukin-10. It also suppresses the expression of chemokines such as macrophage inflammatory protein 1a and 1b and suppresses the expression of pro-inflammatory lipid mediator leukotriene B4 (Serezani et al., 2008).
Autologous Hematopoietic Stem Cell Transplantation for Crohn’s Disease
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Robert M. Craig, Richard K. Burt
Crohn’s disease is an immune-mediated disease. An autoimmune etiology remains controversial and unproven. No intestinal self antigen (initiating or spread epitope) has been identified. On the other hand, several animal gene knockout models suggest that inflammatory bowel disease may be a result of immune dsyregulation between Th1 and Th2 cytokines. Deficiency of multiple Th2 cytokines (such as IL-10, IL-2, TGF-β) may cause colitis. Interleukin-10 deficient mice develop acute and chronic colitis.22 IL-2 deficient,23 double mutant IL-2 and IL-4 deficient, and transforming growth factor beta deficient24 mice develop colitis. When raised in a germ free environment, these gene knockout mice remain disease free. Animal models demonstrate the need for both cytokine imbalance and gut bacterial flora as disease triggers. Infusion of the T cell subset CD4+ CD45 RBhigh into SCID mice causes colitis.25 When raised in a germ free environment, CD4+ CD45 RBhigh SCID mice do not develop disease.26 Infusion of the normal broad T cell repertoire or treatment with IL-10 or anti-Th1 antibodies into a CD4+CDRBhigh SCID mouse induces remission of colitis.25
Current and Rising Concepts in Immunotherapy: Biopharmaceuti cals versus Nanomedicines
Published in Raj Bawa, János Szebeni, Thomas J. Webster, Gerald F. Audette, Immune Aspects of Biopharmaceuticals and Nanomedicines, 2019
Immune cells produce a huge spectrum of compounds named cytokines acting on other cell types and tissues, which constitutes a major part of humoral immunity. Serum cytokine levels are important in diagnostics as they represent potential indicators of organ injury. There is evidence that cancerogenesis is influenced by different MΦ subsets, but the roles of the subsets are not fully understood. Several reports demonstrated that M2-polarized MΦ are frequent in cancer, which can be designated as type 2 tumor-associated macrophages (TAM2). The TAM2 and other immune cells exhibit immunosuppressive functions, such as myeloid-derived suppressor cells, T helper 2 (Th2) cells, and regulatory T (TReg) cells, which are overrepresented in many types of cancer allowing for immune evasion of tumors [17]. Similar to M2-MΦ and TAM2, also TReg produce large amounts of interleukin 10 (IL10) [18]. M2-MΦ additionally produce many other anti-inflammatory cytokines such as the CC chemokine ligand 18 (CCL18), transforming growth factor β (TGF-β), or interleukin 1 receptor antagonist (IL1RA), depending on the subset of M2-MΦ [19]. Currently our unpublished research in experimental liver cancer has demonstrated that in addition to the TAM2, there are also inflammatory TAM, which one might term TAM1, which are highly distinctive from TAM2 and from MDSC in mRNA profiles.
Inflammatory bowel disease: why this provides a useful example of the evolving science of nutrigenomics
Published in Journal of the Royal Society of New Zealand, 2020
One of the genes shown to be involved in the development of CD is Interleukin-10, an immunosuppressive cytokine involved in the regulation of gastrointestinal mucosal immunity toward intestinal microbiota. The interleukin-10-deficient (IL10-/-) mouse is a variant of C57BL/6 mice, that develops intestinal inflammation unless raised in germ-free conditions, and has been used as a mouse model of CD. Lin et al. (2009) used non-targeted urinary profiling to study systemic metabolic changes associated with the development of intestinal inflammation in this mouse. Spot urine samples were collected from IL10-/- and the control mice at 5.5, 7, 8.5, and 10.5 weeks of age. Urine samples were analysed by gas chromatography-mass spectrometry (GCMS), while statistical analysis utilised XCMS software, multiple t tests, and ANOVA. Elevated urinary levels of xanthurenic acid and fucose in IL10-/- mice, relative to those in wild type mice, indicated upregulation of tryptophan catabolism and perturbed fucosylation caused by this mutation. Other data also suggested the downregulation of fatty acid oxidation in the variant mice. These metabolites were thus identified as potential markers of intestinal inflammation. Further investigation of these mouse models (Lin et al. 2010) showed fifteen further metabolite differences, including fucose, xanthurenic acid, and 5-aminovaleric acid, that were associated with intestinal inflammation. Elevated urinary levels of xanthurenic acid in the variant mouse were attributed to an increased production of kynurenine metabolites that may induce T-cell tolerance toward intestinal microbiota.
Histopathological and inflammatory response in multiple organs of rats exposed to crack
Published in International Journal of Environmental Health Research, 2022
Daniel Souza, Barbara Rosarioa, Breno Casagrandea, Milena Viana, Debora Estadella, Rogerio Peres, Camilo Dias Seabra Pereira, Rogerio Peres
Inflammation is an essential mechanism that ensures organism protection against biological, physical and chemical agents, such as narcotics in general. It is known that inflammation also acts in tissue regeneration. Once tissue integrity is restored, inflammatory infiltrate ends. However, if there is any deregulation, inflammation remains, turning into a chronic process (Oishi and Manabe 2018). Cytokines are classified as pro – or anti-inflammatory activities. Tumor necrosis factor alpha (TNF-α), interleukin-1 beta and interleukin-6 (IL-1β and IL-6) activates inflammation, while interleukin-10 (IL-10) has anti-inflammatory activity (Souza et al. 2010).