Characterization of Recombinant Extracellular Domain of Human Interleukin-10 Receptor

Tan, Jimmy; Braun, Serafina; Rong, Hong; DiGiacomo, Ruth; Dolphin, Edward; Baldwin, Samuel; Narula, Satwant K.; Zavodny, Paul J.; Chou, Chuan‐Chu

doi:10.1074/jbc.270.21.12906

Cited by 62 publications

(61 citation statements)

References 40 publications

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“…However, OB-R⌬868 was unable to as efficiently repress signaling by full-length OB-R or the OB-R/G-CSFR chimera. It is therefore possible that leptin binding to cell surface receptors can result in higher order oligomerization (receptor numberϾ2/complex) as has been shown for IL-10 receptor complexes (31) and for members of the activin/transforming growth factor-␤R family (32)(33)(34)(35)(36). According to this model, ligand binding by full-length OB-R or OB-R/G-CSFR chimera can lead to aggregation of more than two receptor chains, yet juxtaposition of only two intracellular domains is sufficient for signal generation.…”

Section: Discussionmentioning

confidence: 99%

Leptin Receptor (OB-R) Signaling

White

Kuropatwinski

Devos

et al. 1997

Journal of Biological Chemistry

260

101

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The leptin receptor (OB-R) mediates the weight regulatory effects of the adipocyte secreted hormone leptin (OB). Previously we have shown that the long form of OB-R, expressed predominantly in the hypothalamus, can mediate ligand-induced activation of signal transducer and activator of transcription factors 1, 3, and 5 and stimulate transcription via interleukin-6 and hematopoietin receptor responsive gene elements. Here we report that deletion and tyrosine substitution mutagenesis of OB-R identifies two distinct regions of the intracellular domain important for signaling. In addition, granulocyte-colony stimulatory factor receptor/OB-R and OB-R/granulocyte-colony stimulatory factor receptor chimeras are signaling competent and provide evidence that aggregation of two OB-R intracellular domains is sufficient for ligand-induced receptor activation. However, signaling by full-length OB-R appears to be relatively resistant to dominant negative repression by signaling-incompetent OB-R, suggesting that mechanisms exist to permit signaling by the long form of OB-R even in the pretence of excess naturally occurring short form of OB-R.Leptin (OB) is an adipose tissue-derived secreted hormone that is thought to suppress appetite by regulating activities of satiety centers in the brain (1). The weight reducing effects of leptin appear to be mediated by interaction with the leptin receptor (OB-R) 1 in the hypothalamus, a region of the brain implicated in the control of body weight (2-4). In mice, mutations in the genes encoding either OB-R (db) or leptin (ob) result in profound early-onset obesity (5, 6). Multiple splice variants of OB-R mRNAs encoding proteins with different length intracellular domains have been detected (7,8). The mutant allele (db) of the OB-R gene was shown to encode a receptor with a truncated cytoplasmic domain (7,8), and more recent data suggest this receptor is signaling inactive (9). Thus, mounting evidence suggests the ability of leptin to regulate body weight is facilitated by downstream signaling events initiated by ligand-induced OB-R activation.Sequence homology and more recent functional data suggest OB-R is a member of the class I cytokine receptor superfamily (4, 10, 11). Receptors of this class lack intrinsic tyrosine kinase activity and are activated by ligand-induced receptor homo-or hetero-dimerization and in many cases require activation of receptor-associated kinases of the Janus family (JAKs) (12). JAKs associate with the membrane-proximal domain of the intracellular part of the cytokine receptors and serve to initiate signal transduction pathways following ligand-induced receptor activation. Included among the downstream targets of the JAK proteins are members of the STAT (Signal Transducers and Activators of Transcription) family of transcription factors (12). The STATs are DNA binding transcription factors that contain Src homology (SH2) domains that interact with receptor molecules through phosphorylated tyrosine residues. STAT proteins are activated by tyrosine phosphorylation...

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Section: Discussionmentioning

confidence: 99%

Leptin Receptor (OB-R) Signaling

White

Kuropatwinski

Devos

et al. 1997

Journal of Biological Chemistry

260

101

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“…IL-10 is expressed in monocytes/macrophages, CD4 ϩ T cells and Th0, Th1, Th2 cell clones, CD8 ϩ T cells and clones, keratinocytes, activated B cells, B lymphomas, and Burkitt lymphoma lines infected with transforming EBC strain (5). In human PBMC, IL-10 inhibits the synthesis of IL-1, IL-6, IL-8, IL-12, and TNF (6). The C-terminal end of human IL-10 contains a 9-aa peptide (Ala-TyrMet-Thr-Met-Lys-Ile-Arg-Asn) that has a tyrosine at position 153.…”

mentioning

confidence: 99%

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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“…IL-10R is a class II cytokine family member composed of 2 subunits: IL-10R1 is the unique ligand-binding subunit and IL-10R2 is the signaling subunit that is shared with other family member cytokines, including IL-22, IL-26, IL-28, and IL-29. [14][15][16] Thus, if the binding sites important for IL-10/IL-10R1 signaling can be determined, it will then be possible to develop drugs (e.g., small organic molecules, peptides, proteins and DNA segments) to block the IL-10 signaling and therefore inhibit the effect of IL-10 overexpression. However, very few clinically useful molecules are suitable for this purpose; one possible reason is that classical small molecules are not always ideal for disrupting protein-protein interactions.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory mechanism of peptides with a repeating hydrophobic and hydrophilic residue pattern on interleukin-10

Wang

Cummins

et al. 2016

Human Vaccines & Immunotherapeutics

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Interleukin 10 (IL-10) is a cytokine that is able to downregulate inflammation. Its overexpression is directly associated with the difficulty in the clearance of chronic viral infections, such as chronic hepatitis B, hepatitis C and HIV infection, and infection-related cancer. IL-10 signaling blockade has been proposed as a promising way of clearing chronic viral infection and preventing tumor growth in animal models. Recently, we have reported that peptides with a helical repeating pattern of hydrophobic and hydrophilic residues are able to inhibit IL-10 significantly both in vitro and in vivo. 1 In this work, we seek to further study the inhibiting mechanism of these peptides using sequence-modified peptides. As evidenced by both experimental and molecular dynamics simulation in concert the N-terminal hydrophobic peptide constructed with repeating hydrophobic and hydrophilic pattern of residues is more likely to inhibit IL10. In addition, the sequence length and the ability of protonation are also important for inhibition activity.

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Characterization of Recombinant Extracellular Domain of Human Interleukin-10 Receptor

Cited by 62 publications

References 40 publications

Leptin Receptor (OB-R) Signaling

Leptin Receptor (OB-R) Signaling

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

Inhibitory mechanism of peptides with a repeating hydrophobic and hydrophilic residue pattern on interleukin-10

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