Disease relevance of Il10

• We report that colitis was dependent on TLR signaling in Il10(-/-) mice [1].
• Thus, combined administration of mouse Il4 and Il10 plasmids prevents the development of autoimmune diabetes in NOD mice [2].
• Experiments using Il10 knockout mice, for which no differences between the susceptibilities of males and females to Listeria infection could be detected, confirmed the important role of this immunosuppressive cytokine for the outcome of disease [3].
• These data implicate IL-10 as a candidate for treatment of bacterial sepsis, and more generally as an effective antiinflammatory reagent [4].
• Mice rendered deficient in the production of interleukin 10 (IL-10-/-) develop a chronic inflammatory bowel disease (IBD) that predominates in the colon and shares histopathological features with human IBD [5].
• We demonstrate that increased IL-13 receptor alpha 2 (IL-13Ralpha2) expression is responsible for the reduced AHR, mucus production, and fibrosis in BALB/c IL-10(-/-) mice [6].
• These data demonstrate that P. gingivalis-induced periodontitis in IL-10-deficient mice is dependent upon IL-12p40-mediated proinflammatory T cell responses [7].

Psychiatry related information on Il10

• Maternal administration of perphenazine decreased the incidence of cannibalism in colonies of interferon-gamma, interleukin (IL-4, IL-10, and IL-12) knockout mice of the DBA/1 and C57BL/6 background strains [8].
• Interleukin (IL)-1 and tumor necrosis factor (TNF) promote slow-wave sleep (SWS), whereas IL-10 inhibits the synthesis of IL-1 and TNF and promotes waking [9].
• Interleukin-10 (IL-10) but not Lipopolysaccharide (LPS) produces increased motor activity and abnormal exploratory patterns while impairing spatial learning in Balb/c mice [10].

High impact information on Il10

• IL-10 inhibits antigen-presenting cell (APC)-induced lymphokine production by TH1 cells but not by TH2 cells [11].
• Interleukin-10 (IL-10) affects the growth and differentiation of many hemopoietic cells in vitro; in particular, it is a potent suppressor of macrophage and T cell functions [12].
• In IL-10-deficient mice, generated by gene targeting, lymphocyte development and antibody responses are normal, but most animals are growth retarded and anemic and suffer from chronic enterocolitis [12].
• Interleukin-10-deficient mice develop chronic enterocolitis [12].
• Paradoxically, IL-10, another CD40-induced cytokine in macrophages, promotes Leishmania infection [13].

Chemical compound and disease context of Il10

• Kupffer cells from BDL mice produced low levels of IL-12p40 and high levels of IL-10 in vitro in response to lipopolysaccharide derived from E. coli [14].
• Interleukin-10 controls neutrophilic infiltration, hepatocyte proliferation, and liver fibrosis induced by carbon tetrachloride in mice [15].
• Substance P regulates Th1-type colitis in IL-10 knockout mice [16].
• IL-10(-/-) mice given piroxicam develop severe and persistent colitis [17].
• AIMS: To test whether the peroxisome proliferator-activated receptor gamma (PPARgamma) ligand rosiglitazone (Ro) has therapeutic activity in the IL-10(-/-) mouse model of inflammatory bowel disease (IBD), and to identify the cellular targets and molecular mechanisms of Ro action [18].

Genetic context of IL-10

• Production of IL-10 is controlled by loci Cypr2 (chromosome 1) and Cypr3 (chromosome 5) [19].

Biological context of Il10

• In the liver of NOD mice, we detected mouse Il4 and Il10 mRNA 5 days after intravenous injection of both PAGA-Il4 and PAGA-Il10 plasmid complexes [2].
• In addition, three main effect QTLs on chromosomes 4, 5, and 12 were identified in the backcross to C57BL/6J-Il10(-/-) [20].
• It further shows that caution should be observed when analyzing the effects of knockout/congenic strains because many of the gene expression differences in these comparisons could not be attributable to the ablated Il10 gene but rather to passenger gene effects [21].
• Finally, IL-10 did not upregulate class II MHC antigens on B cells from X chromosome-linked immunodeficiency (XID) mice, while the same cells showed normal upregulation of class II antigens in response to IL-4 [22].
• These mice will be useful in defining differences in inflammatory conditions and cellular immunity mediated by IL-10 [23].

Anatomical context of Il10

• Genetic removal of Il10 resulted in the maintenance of robust effector T-cell responses, the rapid elimination of virus and the development of antiviral memory T-cell responses [24].
• ATMs from lean mice expressed many genes characteristic of M2 or "alternatively activated" macrophages, including Ym1, arginase 1, and Il10 [25].
• However, these CD8- cells produced large amounts of IL-4, IL-5, and IL-10 and helped activate resting B cells [26].
• Upon in vitro stimulation, spleen cells from unimmunized transgenic mice secrete higher levels of IL-10 and lower amounts of IFN-gamma than do controls, although no gross abnormalities were detected in lymphocyte populations or serum Ig levels [23].
• In further studies in vitro, it was shown that IL-10 blocked the ability of IFN-gamma to inhibit the intracellular replication of T. cruzi in mouse peritoneal macrophages [27].

Associations of Il10 with chemical compounds

• Inhibition of HO-1 protein synthesis or activity significantly reversed the inhibitory effect of IL-10 on production of tumor necrosis factor-alpha induced by lipopolysaccharide (LPS) [28].
• Additional experiments revealed the involvement of carbon monoxide, one of the products of HO-1-mediated heme degradation, in the anti-inflammatory effect of IL-10 in vitro [28].
• Dimerization of Stat3-GyrB by coumermycin mimicked the effect of IL-10, and expression of DeltaStat3 blocked the anti-proliferative activity of IL-10 [29].
• BMMCs stimulated by KL + IL-10 for 10 h exhibited a delayed phase of PGD2 generation, which was dependent on de novo induction of PGHS-2 [30].
• The role of the anti-inflammatory cytokine interleukin-10 (IL-10) was investigated in the mouse model of liver injury induced by carbon tetrachloride (CCl4) [15].

Physical interactions of Il10

• IL-10 pretreatment of myeloid DCs cultured from bone marrow resulted in reduced DNA binding and nuclear translocation of NF-kappaB after anti-CD40 antibody or lipopolysaccharide (LPS) stimulation [31].
• Furthermore, TCR cross-linking of DN Treg cells in the presence of IL-10 leads to the up-regulation of the membrane-bound but not the soluble form of TNF-alpha [32].
• The binding of Sp1 and C/EBPdelta as a complex to the Sp1 binding site on the promoter of IL-10 was further confirmed by using the DNA affinity precipitation assay [33].
• Critical role of the major histocompatibility complex and IL-10 in matrilin-1-induced relapsing polychondritis in mice [34].

Regulatory relationships of Il10

• Instead, IL-1beta slowed by approximately 8-fold the decay of IL-6 mRNA as compared to its decay in BMMC stimulated with KL + IL-10 alone [35].
• The IkappaB protein Bcl-3 negatively regulates transcription of the IL-10 gene in macrophages [36].
• However, we observed that mRNA for the T helper 2 cytokine IL-10 was suppressed in the Peyer's patches and mesenteric lymph nodes and IL-4 mRNA was suppressed in the mesenteric lymph nodes compared to noninfected controls, following oral infection [37].
• The suppressive effect of prostaglandin E2 lasted for more than 36 h while IL-10 blocked tumor necrosis factor-alpha production for barely 24 h [38].
• We show that concurrent expression of IL-10 inhibited GM-CSF-driven OVA-specific inflammation in a dose-dependent manner [39].

Other interactions of Il10

• Unlike wild-type mice, IFN-gamma-deficient, inducible nitric oxide synthase (iNOS)-deficient, and Bcl-2(lck) transgenic mice were poorly protected by IL-12, whereas IL-10-deficient mice were protected [40].
• The protective effect of IL-10 was reversed by prior injection of neutralizing anti-IL-10 antibodies, and correlated with a substantial decrease in endotoxin-induced TNF-alpha release [4].
• Inhibition of cytokine expression by CSIF is not due to a general reduction in Th1 cell viability, since actin mRNA levels were not reduced, and proliferation of antigen-stimulated cells in response to IL-2, was unaffected [41].
• Distinct contribution of IL-6, TNF-alpha, IL-1, and IL-10 to T cell-mediated spontaneous autoimmune arthritis in mice [42].
• Decreased graft survival in IL-10 -/- recipients was associated with increases in iNOS and IFN-gamma-driven responses [43].

Analytical, diagnostic and therapeutic context of Il10

• A single injection of 0.5-1 microgram of recombinant murine IL-10 reproducibly protected BALB/c mice from a lethal intraperitoneal injection of endotoxin [4].
• To study the role of cytokines in long-term cardiac allografts we have used recipient mice with targeted gene deletions (-/-) in IFN-gamma, IL-4, or IL-10 [43].
• Interleukin-10 expression and chemokine regulation during the evolution of murine type II collagen-induced arthritis [44].
• In mice, IL-10 suppresses tumorigenicity in a xenograft system using a nonmetastasizing hamster cell line [45].
• IMPLICATIONS: Based on the recent observation of others that IL-10 has little toxicity when administered systemically to human volunteers and also on the findings of this study that it has antitumor and antimetastitic properties in mice, possible use of IL-10 in the treatment of human metastatic cancers deserves consideration [45].

References