Identification of functional domains on human interleukin 10

Gesser, Borbala; Leffers, Henrik; Jinquan, Tan; Vestergaard, Christian; Kirstein, Nicka; Sindet‐Pedersen, Steen; Jensen, S. L.; Thestrup‐Pedersen, Kristian; Larsen, Christian Grónhøj

doi:10.1073/pnas.94.26.14620

Cited by 71 publications

(66 citation statements)

References 26 publications

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“…Peroxynitrite nitrates tyrosine residues (13). A tyrosine residue at aa 153 in the presumptive functional domain is a potential target site for the interaction of IL-10 and peroxynitrite (7). These results are consistent with tyrosine nitration by peroxynitrite as a mechanism for enhancement of IL-10 activity.…”

Section: Discussionsupporting

confidence: 77%

“…The experiments with DTT suggest that thiol formation is not sufficient to explain the increase in activity. This is consistent with the lack of cysteines at the presumed active site (7). If formation of 3-nitrotyrosine on IL-10 were the mechanism of enhancement, other mechanisms of nitration such as nitrite and myeloperoxidase would presumably do the same (26).…”

Section: Discussionsupporting

confidence: 60%

“…However, peroxynitrite may potentially affect protein function by other mechanisms including nitration of methionine (23). The presumed active site of human IL-10 contains two methionines (7). Also nitration of tryptophan (24) or formation of S-nitrosothiol groups on cysteines (25) can occur with peroxynitrite.…”

Section: Discussionmentioning

confidence: 99%

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Enhanced Activity of Human IL-10 After Nitration in Reducing Human IL-1 Production by Stimulated Peripheral Blood Mononuclear Cells

Freels

Nelson

Hoyt

et al. 2002

The Journal of Immunology

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Nitric oxide and superoxide form the unstable compound, peroxynitrite, which can nitrate proteins and compromise function of proinflammatory cytokines at sites of inflammation. Reduced function of proinflammatory proteins such as IL-8, macrophage inflammatory protein-1α, and eotaxin suggest an anti-inflammatory effect of nitration. The effects of nitration on anti-inflammatory cytokines such as IL-10 are unknown. We hypothesized that peroxynitrite would modify the function of anti-inflammatory cytokines like IL-10. To test this hypothesis, the capacity of recombinant human IL-10 to inhibit production of human IL-1β (IL-1) from LPS-stimulated human PBMC was evaluated. Human IL-10 was nitrated by incubation with peroxynitrite or by incubation with 3-morpholinosydnonimine, a peroxynitrite generator, for 2 h and then incubated with LPS-stimulated PBMC for 6 h, and IL-1 was measured in the culture supernatant fluids. Human IL-1 production was significantly lower in the peroxynitrite- or 3-morpholinosydnonimine-nitrated IL-10 group than in the IL-10 controls (p < 0.05, all comparisons). This finding demonstrates that although peroxynitrite inhibits proinflammatory cytokines, it may augment anti-inflammatory cytokines and further point to an important role for peroxynitrite in the regulation of inflammation.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionsupporting

confidence: 60%

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Enhanced Activity of Human IL-10 After Nitration in Reducing Human IL-1 Production by Stimulated Peripheral Blood Mononuclear Cells

Freels

Nelson

Hoyt

et al. 2002

The Journal of Immunology

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Section: Il-19 Induces Production Of Il-6 and Tnf-␣ And Results Inmentioning

confidence: 99%

“…IL-10 was originally described as a cytokine synthesis-inhibitory factor due to its inhibitory effect on cytokine production (2). Because IL-10 suppresses the release and function of a number of proinflammatory cytokines such as IL-1, TNF-␣, and IL-6, it is a normal endogenous feedback factor for the control of immune responses and inflammation (2,3). Autoimmune models of rheumatoid arthritis, thyroiditis, and collagen-induced arthritis and a model of herpetic stromal keratitis all suggest negative regulatory roles of IL-10 in limiting inflammation and immunopathology (3).…”

Section: Il-19 Induces Production Of Il-6 and Tnf-␣ And Results Inmentioning

confidence: 99%

IL-19 Induces Production of IL-6 and TNF-α and Results in Cell Apoptosis Through TNF-α

Liao

Liang

Chen

et al. 2002

The Journal of Immunology

300

228

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IL-10 is an immunosuppressive cytokine in the immune system. It was in clinical trail as an anti-inflammatory therapy for inflammatory bowel disease and various autoimmune diseases such as psoriasis, rheumatoid arthritis, and multiple sclerosis. IL-19 belongs to the IL-10 family, which includes IL-10, IL-19, IL-20, IL-22, melanoma differentiation-associated gene (MDA-7, IL-24), and AK155 (IL-26). Despite a partial homology in their amino acid sequences, they are dissimilar in their biologic functions. Little is known about the biologic function and gene regulation of IL-19. To understand the gene regulation of human IL-19, we identified a human IL-19 genomic clone and analyzed its promoter region. Five fusion genes containing different regions upstream of exon 1 linked to a luciferase reporter gene were expressed in the canine kidney epithelial-like Madin-Darby canine kidney cells. A fusion gene containing 394 bp showed luciferase activity 7- to 8-fold higher than the negative control of the promoterless fusion gene. We also isolated a full-length mouse cDNA clone. Mouse IL-19 shared 71% amino acid identity with human IL-19. Treatment of monocytes with mouse IL-19 induced the production of IL-6 and TNF-α. It also induced mouse monocyte apoptosis and the production of reactive oxygen species. Taken together, our results indicate that mouse IL-19 may play some important roles in inflammatory responses because it up-regulates IL-6 and TNF-α and induces apoptosis.

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T cell stimulation upon long-term secretion of viral IL-10

1999

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Viral IL‐10 (vIL‐10), the IL‐10 homologue of Epstein‐Barr virus, has so far been described as a cytokine that solely inhibits T cell function. Here we show in vivo and in vitro that after long‐term secretion vIL‐10 has a stimulatory effect on T cells. For this purpose we employed transfectants derived from a mastocytoma cell line (P815 cells, H‐2d) constitutively secreting vIL‐10 (P815‐vIL‐10) or expressing the co‐stimulatory molecule B7‐1 (P815‐B7). After in vitro stimulation of splenocytes from syngeneic DBA/2 mice for 7 days in the presence of P815‐vIL‐10 cells we could detect a marked reduction of proliferation as well as cytotoxicity against P815 target cells. However, this inhibitory effect was reversed when stimulation with P815‐vIL‐10 cells was extended to 14 days. In vivo P815‐vIL‐10 cells were rejected whereas P815 cells transfected with a control plasmic were tumorigenic after injection into syngeneic DBA/2 mice. Furthermore, this stimulatory effect of constitutive vIL‐10 secretion could be exploited to irradicate already established P815 tumors which were smaller than 5 × 5 mm. In contrast, paracrine vIL‐10 secretion for a limited time period of 8 – 9 days was associated with inhibitory effects in vivo: P815‐B7 cells, which are normally eliminated in DBA/2 mice, could grow if exposed to temporarily secreted vIL‐10. These time‐dependent immunomodulatory effects have to be considered in potential therapeutic applications of vIL‐10.

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Identification of functional domains on human interleukin 10

Cited by 71 publications

References 26 publications

Enhanced Activity of Human IL-10 After Nitration in Reducing Human IL-1 Production by Stimulated Peripheral Blood Mononuclear Cells

Enhanced Activity of Human IL-10 After Nitration in Reducing Human IL-1 Production by Stimulated Peripheral Blood Mononuclear Cells

IL-19 Induces Production of IL-6 and TNF-α and Results in Cell Apoptosis Through TNF-α

T cell stimulation upon long-term secretion of viral IL-10

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