The Molecular Basis of IL-10 Function: from Receptor Structure to the Onset of Signaling

Walter, Mark R.

doi:10.1007/978-3-662-43492-5_9

Cited by 93 publications

(99 citation statements)

References 93 publications

(171 reference statements)

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“…Previous literature characterizes IL10 as immunosuppressive [16] and finds only positive associations between serum IL10 [17] or genetic expression of IL10RB [15] and glioma. However, IL10 may also stimulate the immune system thereby playing a role in tumor immune surveillance [32]. IL10 knockout mice showed weakened tumor immune surveillance [33].…”

Section: Discussionmentioning

confidence: 99%

A nested case-control study of 277 prediagnostic serum cytokines and glioma

et al. 2017

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Recent research shows bidirectional communication between the normal brain and the peripheral immune system. Glioma is a primary brain tumor characterized by systemic immunosuppression. To better understand gliomagenesis, we evaluated associations between 277 prediagnostic serum cytokines and glioma. We used glioma (n = 487) and matched control (n = 487) specimens from the Janus Serum Bank Cohort in Oslo, Norway. Conditional logistic regression allowed us to identify those cytokines that were individually associated with glioma. Next, we used heat maps to compare case to control Pearson correlation matrices of 12 cytokines modeled in an in silico study of the interaction between the microenvironment and the tumor. We did the same for case-control correlation matrices of lasso-selected cytokines and all 277 cytokines in the data set. Cytokines related to glioma risk (P ≤ .05) more than 10 years before diagnosis are sIL10RB, VEGF, beta-Catenin and CCL22. LIF was associated with decreased glioma risk within five years before glioma diagnosis (odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.23, 0.94). After adjustment for cytokines above, the previously observed interaction between IL4 and sIL4RA persisted (> 20 years before diagnosis, OR = 1.72, 95% CI = 1.20, 2.47). In addition, during this period, case correlations among 12 cytokines were weaker than were those among controls. This pattern was also observed among 30 lasso- selected cytokines and all 277 cytokines. We identified four cytokines and one interaction term that were independently related to glioma risk. We have documented prediagnostic changes in serum cytokine levels that may reflect the presence of a preclinical tumor.

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Section: Discussionmentioning

confidence: 99%

A nested case-control study of 277 prediagnostic serum cytokines and glioma

et al. 2017

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“…We specifically targeted the IL-10R1/subunit alpha for knockdown because of its main role in the binding of IL-10 and the assembling of the IL-10R receptor complex [6,25,53]. Besides its contribution to the IL-10R complex, IL-10R2 (beta subunit) also associates with IL-20 R alpha, IL-22 R alpha or IL-28 R alpha to form the receptor complexes for IL-22, IL-26, IL-28, and IL-29 [53], making it unsuitable as specific target for our experimental knockdown approach.…”

Section: Discussionmentioning

confidence: 99%

“…Local IL-10 acts on a number of different cell populations, including macrophages, neutrophils and skeletal muscle fibers, orchestrating muscle growth and regeneration after injury [16]. These IL-10 effects depend on its interaction with a heterodimer receptor complex, constituted by the high affinity subunit 1 (IL-10R1, also called subunit alpha) which is necessary for the binding of IL-10 [28,53], and the low-affinity IL-10 receptor 2 (IL-10R2, also called subunit beta and previously referred to as CRFB4), which is essential for IL-10 induced signal transduction events [25,53]. Interestingly, IL-10R1/subunit alpha, is expressed in dorsal root ganglia (DRG) [46] and intrathecal administration of recombinant IL-10 or adenoviral vectors containing IL-10 cDNA attenuates increased excitability of DRG neurons and abnormal nociceptive behavior in diverse neuropathic pain models [26,33,34,46,55].…”

Section: Introductionmentioning

confidence: 99%

Nociceptor interleukin 10 receptor 1 is critical for muscle analgesia induced by repeated bouts of eccentric exercise in the rat

Álvarez

Bogen

Green

et al. 2017

PAIN

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Delayed-onset muscle soreness is typically observed after strenuous or unaccustomed eccentric exercise. Soon after recovery, blunted muscle soreness is observed on repeated eccentric exercise, a phenomenon known as repeated bout effect (RBE). Although regular physical activity decreases muscle hyperalgesia, likely because of increased production of the anti-inflammatory cytokine interleukin-10 (IL-10) in the skeletal muscle, whether IL-10 also contributes to the antinociceptive effect of RBE is unknown. Furthermore, whether IL-10 attenuates muscle hyperalgesia by acting on muscle nociceptors remains to be established. Here, we explored the hypothesis that blunted muscle nociception observed in RBE depends on a local effect of IL-10, acting on IL-10 receptor 1 (IL-10R1) expressed by muscle nociceptors. Results show that after a second bout of eccentric exercise, rats exhibited decreased muscle hyperalgesia, indicative of RBE, and increased expression of IL-10 in the exercised gastrocnemius muscle. Although knockdown of IL-10R1 protein in nociceptors innervating the gastrocnemius muscle by intrathecal antisense oligodeoxynucleotide did not change nociceptive threshold in naive rats, it unveiled latent muscle hyperalgesia in rats submitted to eccentric exercise 12 days ago. Furthermore, antisense also prevented the reduction of muscle hyperalgesia observed after a second bout of eccentric exercise. These data indicate that recovery of nociceptive threshold after eccentric exercise and RBE-induced analgesia depend on a local effect of IL-10, acting on its canonical receptor in muscle nociceptors.

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“…Immune-modulating strategies of persistence by "hit-andstay" pathogens are likely to be fundamentally different from acute, or "hit-and-run," pathogens, for which viral replication and intra-and interhost dissemination mostly transpire prior to development of de novo adaptive immune responses that could potentially clear the pathogen (1). Cellular interleukin-10 (cIL-10) is an anti-inflammatory cytokine that is considered a master regulator of the immune system due to its positive and negative effects on cells bearing the IL-10 receptor (IL-10R) (2). Manipulation of the cIL-10/IL-10R signaling pathway has been increasingly associated with long-term persistent infections in immunocompetent hosts (3).…”

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confidence: 99%

“…Taken together, host immunity mostly protects against HCMV disease during primary infection, but host immune responses are insufficient to clear persistent reservoirs in infected hosts, despite extraordinarily large HCMV-specific T cell responses (11) and the induction of neutralizing antibodies against multiple HCMV glycoproteins (4,(12)(13)(14). The viral mechanisms of persistence are incompletely resolved, but there is increasing evidence that cIL-10 signaling through binding to its high-affinity receptor (IL-10R1) is critical for maintaining persistence (2,3). Studies of MCMV-infected mice revealed that there is a marked increase in the number of CD4 ϩ cells expressing cIL-10 in tissue sites of persistence (salivary glands) but not in tissues where MCMV establishes a latent infection (e.g., spleen) (7).…”

mentioning

confidence: 99%

Exploitation of Interleukin-10 (IL-10) Signaling Pathways: Alternate Roles of Viral and Cellular IL-10 in Rhesus Cytomegalovirus Infection

Eberhardt

Deshpande

Fike

et al. 2016

J Virol

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There is accumulating evidence that the viral interleukin-10 (vIL-10) ortholog of both human and rhesus cytomegalovirus (HCMV and RhCMV, respectively) suppresses the functionality of cell types that are critical to contain virus dissemination and help shape long-term immunity during the earliest virus-host interactions. In particular, exposure of macrophages, peripheral blood mononuclear cells, monocyte-derived dendritic cells, and plasmacytoid dendritic cells to vIL-10 suppresses multiple effector functions including, notably, those that link innate and adaptive immune responses. Further, vaccination of RhCMV-uninfected rhesus macaques with nonfunctional forms of RhCMV vIL-10 greatly restricted parameters of RhCMV infection following RhCMV challenge of the vaccinees. Vaccinees exhibited significantly reduced shedding of RhCMV in saliva and urine following RhCMV challenge compared to shedding in unvaccinated controls. Based on the evidence that vIL-10 is critical during acute infection, the role of vIL-10 during persistent infection was analyzed in rhesus macaques infected long term with RhCMV to determine whether postinfection vaccination against vIL-10 could change the virus-host balance. RhCMV-seropositive macaques, which shed RhCMV in saliva, were vaccinated with nonfunctional RhCMV vIL-10, and shedding levels of RhCMV in saliva were evaluated. Following robust increases in vIL-10-binding and vIL-10-neutralizing antibodies, shedding levels of RhCMV modestly declined, consistent with the interpretation that vIL-10 may play a functional role during persistent infection. However, a more significant association was observed between the levels of cellular IL-10 secreted in peripheral blood mononuclear cells exposed to RhCMV antigens and shedding of RhCMV in saliva. This result implies that RhCMV persistence is associated with the induction of cellular IL-10 receptor-mediated signaling pathways. IMPORTANCEHuman health is adversely impacted by viruses that establish lifelong infections that are often accompanied with increased morbidity and mortality (e.g., infections with HIV, hepatitis C virus, or human cytomegalovirus). A longstanding but unfulfilled goal has been to develop postinfection vaccine strategies that could "reboot" the immune system of an infected individual in ways that would enable the infected host to develop immune responses that clear reservoirs of persistent virus infection, effectively curing the host of infection. This concept was evaluated in rhesus macaques infected long term with rhesus cytomegalovirus by repeatedly immunizing infected animals with nonfunctional versions of the rhesus cytomegalovirus-encoded viral interleukin-10 immune-modulating protein. Following vaccine-mediated boosting of antibody titers to viral interleukin-10, there was modest evidence for increased immunological control of the virus following vaccination. More significantly, data were also obtained that indicated that rhesus cytomegalovirus is able to persist due to upregulation of the cellular interleukin-...

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The Molecular Basis of IL-10 Function: from Receptor Structure to the Onset of Signaling

Cited by 93 publications

References 93 publications

A nested case-control study of 277 prediagnostic serum cytokines and glioma

A nested case-control study of 277 prediagnostic serum cytokines and glioma

Nociceptor interleukin 10 receptor 1 is critical for muscle analgesia induced by repeated bouts of eccentric exercise in the rat

Exploitation of Interleukin-10 (IL-10) Signaling Pathways: Alternate Roles of Viral and Cellular IL-10 in Rhesus Cytomegalovirus Infection

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