ライフサイエンスコーパス: IL-10R

1 IL-10R blockade maintained IL-12 protein 40, markedly in

2 IL-10R blockage abolished PPAR-gamma-mediated inhibition

3 IL-10R deficiency was confirmed by functional assays on

4 c domain of the receptor for interleukin 10 (IL-10R) contains two box 3 sequence motifs that have bee

5 cently identified the interleukin-10 (IL-10)/IL-10R pathway as a key regulator of acute versus chroni

6 ction, as neutralizing antibodies for IL-10, IL-10R, and TGF-beta were unable to revert suppression,

7 ectional IL-10-dependent loop, then an IL-10-IL-10R pathway defect could abrogate the anti-inflammato

8 In this way, a genetic IL-10-IL-10R pathway defect could interact with an environment

9 Thus, a functional IL-10-IL-10R pathway was essential for 1,25-(OH)(2)D(3) to inh

10 ce from lethal intestinal damage in an IL-10-IL-10R-dependent manner.

11 ing in inhibition of the interleukin (IL)-10/IL-10R autocrine/paracrine cytokine autoregulatory loop

12 eceptor 4-induced, autocrine/paracrine IL-10/IL-10R activation promoted the expression of hepcidin, t

13 In contrast, autocrine/paracrine IL-10/IL-10R activation repressed the expression of cathelicid

14 Because the defect in patients with IL-10/IL-10R deficiency resides in hematopoietic lineage cells

15 supports the concept that induction of IL-10/IL-10R signaling drives a complex immune evasion strateg

16 We sought to gather clinical data of IL-10/IL-10R-deficient patients and devise guidelines for diag

17 IL-10/IL-10R-deficient patients had intractable enterocolitis,

18 Medical records of IL-10/IL-10R-deficient patients were reviewed and compiled.

19 ligands that compelled assembly of an IL-2R/IL-10R heterodimer, which does not naturally exist, that

20 s directly recruited to the ligand-activated IL-10R by binding to specific phosphotyrosine groups whi

21 est the existence of at least one additional IL-10R subunit.

22 nits: IFN-alpha R beta L, IFN-gamma R alpha, IL-10R alpha, IL-2R beta, and IL-4R alpha.

23 Therapeutic administration of an IL-10R blocking Ab enhanced control of the recrudescent

24 nal disease should be screened for IL-10 and IL-10R deficiency and that allogeneic HSCT can induce re

25 fied loss of function mutations in IL-10 and IL-10R in patients with very early onset IBD.

26 the lungs, whereas IFN-gamma, TNF-alpha, and IL-10R remain unchanged from wild type.

27 in experimental visceral leishmaniasis, and IL-10R blockade represents a potential immuno- and/or im

28 d in normal alveolar epithelium of mice, and IL-10R were constitutively expressed on normal murine AM

29 Anti-IL-10R blocks RMTC-mediated modulation of EAE and suppre

30 Anti-IL-10R mAb treatment further suppressed parasite growth

31 Anti-IL-10R therapy reversed the tolerogenic effects of the d

32 ocytes treated in vitro with anti-IL-10/anti-IL-10R were unable to protect recipient mice from develo

33 Furthermore, administration of an anti-IL-10R mAb to unmanipulated adult mice was sufficient to

34 evels of IL-10 were neutralized with an anti-IL-10R mAb.

35 Neutralizing anti-IL-10 and anti-IL-10R, but not anti-TGF-beta, anti-IL-4, or anti-CTLA-4

36 n part to increased IL-10 signaling, as anti-IL-10R Ab treatment reduced median survival time to leve

37 However, because anti-IL-10R also released IFN-gamma-independent effects, IL-1

38 urther and dramatically reduced in both anti-IL-10R-treated IL-4R alpha(-/-) mice and IL-4R alpha x I

39 T cells, and regulation was reversed by anti-IL-10R antibody.

40 IL-10 signaling was blocked (either by anti-IL-10R mAb treatment or by using IL-10-deficient mice).

41 , inflammation in H. hepaticus-infected anti-IL-10R-treated mice, demonstrating a pathogenic role for

42 normal mice with established infection, anti-IL-10R treatment was remarkably active, inducing near-cu

43 T cell-dependent colitis, one involving anti-IL-10R monoclonal antibody treatment of infected T cell-

44 However, in IFN-gamma knockout mice, anti-IL-10R also induced both granuloma formation and leishma

45 nist 1-methyltryptophan or neutralizing anti-IL-10R from days 12 to 21 after DC10 therapy partially r

46 -10(+/+) mice treated with neutralizing anti-IL-10R monoclonal antibody were able to survive lethal c

47 Administration of anti-IL-10R Ab into GM-CSF-treated mice abrogated GM-CSF-indu

48 In contrast, coadministration of anti-IL-10R and TGF-beta mAbs had little effect upon parasite

49 Th1 recall responses in the presence of anti-IL-10R mAb, as removal of LPS abrogated this effect.

50 sive transfer with either anti-IL-10 or anti-IL-10R mAb.

51 In fact, systemic anti-IL-10R Ab treatment prevented viral reactivation in up t

52 Upon systemic anti-IL-10R Ab treatment, we observed a significant expansion

53 blockade studies in mice revealed that anti-IL-10R mAb treatment during acute infection modestly inc

54 monstrate in this study using transient anti-IL-10R treatment that it is the presence of IL-10 in viv

55 tide antigen administered together with anti-IL-10R and LPS.

56 findings were made in mice treated with anti-IL-10R antibody and infected with RSV.

57 as well as wild-type mice treated with anti-IL-10R blocking antibody.

58 th factor (TGF)-beta, as treatment with anti-IL-10R but not anti-TGF-beta monoclonal antibody abrogat

59 rmal mice treated prophylactically with anti-IL-10R demonstrated accelerated granuloma assembly and r

60 llowing BCG vaccination concurrent with anti-IL-10R mAb treatment was sustained through chronic M. tu

61 in IL-4Ralpha(-/-) mice, treatment with anti-IL-10R mAb virtually eliminated L. major parasites in bo

62 IL-4R alpha(-/-) mice were treated with anti-IL-10R mAb, and in a genetic approach, the IL-4R alpha(-

63 letion or treatment of BALB/c mice with anti-IL-10R mAb.

64 e protein antigen was administered with anti-IL-10R mAb; however, this was not the case with peptide

65 r, Pi3k-gamma(-/-) mice pretreated with anti-IL-10R were resistant to C. jejuni-induced intestinal in

66 ing were performed on mice treated with anti-IL-10R-blocking Ab at 3, 6, and 9 d postinfection (dpi)

67 he defined IL-10R, which we now designate as IL-10R alpha.

68 iologic responses only to hIL-10 by both BaF-IL-10R transfectants and normal human peripheral blood c

69 g the chronic phase of infection, we blocked IL-10R in chronically infected mice.

70 reversed by adding neutralizing Abs to both IL-10R and TGF-beta2.

71 The mucosa-specific protection afforded by IL-10R blockade was associated with an increased accumul

72 As judged by IL-10R blockade, endogenous IL-10 primarily regulates ki

73 ent immune regulation, partially mediated by IL-10R-signaling, prevented enhanced disease.

74 T-cell reactivation and not sensitization by IL-10R(-/-) DCs leads to enhanced CHS.

75 cmvIL-10 were investigated, and the classic IL-10R/JAK1/Stat3 pathway was found to be activated in m

76 In contrast, IL-10R(-/-) DCs produced increased levels of proinflamma

77 impaired in its ability to bind the defined IL-10R, which we now designate as IL-10R alpha.

78 ninflammatory hemopoietic cells also express IL-10Rs.

79 CD138(+) MPhi expressed IL-10R, CD206, and CCR2 but little TNF-alpha or CX3CR1.

80 n CD25 and Bcl-2 were not observed following IL-10R blockade.

81 everity in the absence of IL-10 or following IL-10R blockade.

82 s well as native retina expressed functional IL-10R as determined by immunoblot analysis and by the a

83 enitor promyeloid cells expressed functional IL-10Rs, as assessed by precipitation of a 110-kDa prote

84 Hence, IL-10R deficiency is associated with a high risk of deve

85 COS-1 cells, co-expressing the human IL-10R and individual STAT proteins, confirmed a prefere

86 is and inefficient early trafficking of IL10/IL-10R complexes.

87 llectively, our studies define innate immune IL-10R signaling as a key factor regulating mucosal immu

88 tion and IL-1beta secretion was abrogated in IL-10R-deficient macrophages.

89 y TLRs was not associated with a decrease in IL-10R expression, but did require expression of the mye

90 ti-inflammatory macrophages were observed in IL-10R-deficient patients with very early onset inflamma

91 LR2, TLR4, or TLR9 was sufficient to inhibit IL-10R signal transduction, including phosphorylation an

92 Instead, IL-10R blockade increased intratumoral dendritic cell ex

93 Interestingly, IL-10R blockade during acute RSV infection altered CD4(+

94 D8(+) T cells is regulated by cell-intrinsic IL-10R signaling, with implications for immunotherapy.

95 to both hIL-10 and vIL-10 require the known IL-10R, and suggest the existence of at least one additi

96 Expression of the regulatory molecules IL-10R, SIRP-alpha/beta, CD47, CD200R, and CD200L was me

97 otifs, as shown by the analysis of the mouse IL-10R constructs containing progressively truncated cyt

98 the rat retinal sections to identify native IL-10R.

99 ress CD4(+) T cells with a dominant-negative IL-10R.

100 significantly inhibited with a neutralizing IL-10R Ab.

101 The similar actions of IL-10R and IL-6R on the induction of endogenous IL-6-res

102 se observations establish that activation of IL-10R promotes survival of RGCs and this survival-promo

103 Blockade of IL-10R by Ab or genetic deficiency of IL-10 resulted in

104 Blockade of IL-10R converted a chronic LCMV infection into a rapidly

105 Interestingly, in vivo blockade of IL-10R did not affect GM-CSF-induced expansion of CD4(+)

106 ls within the liver, and in vivo blockade of IL-10R resulted in a decreased percentage of intrahepati

107 losis-susceptible CBA/J mice, Ab blockade of IL-10R specifically during BCG vaccination resulted in a

108 tudy, we have determined the contribution of IL-10R signaling to the regulation of immune responses d

109 Importantly, the pathogenic effects of IL-10R blockade during P. berghei ANKA infection were re

110 Our findings underscore the importance of IL-10R signaling in preventing T-cell- and cytokine-medi

111 While infusion of IL-10R blocking antibody, initiated at day 60, caused a

112 Inhibition of IL-10R function by TLRs was not associated with a decrea

113 Mechanistically, inhibition of IL-10R signaling altered chromatin accessibility and dis

114 findings demonstrate that internalization of IL-10R with the resultant impact on IL-10 signaling and

115 findings demonstrate that internalization of IL-10R with the resultant impact on IL-10 signaling and

116 protein kinase Cbeta and internalization of IL-10R, and was independent of TLR2 and phagocytosis.

117 Moreover, loss of IL-10R signaling impaired the generation and function of

118 Low IL10 expression or loss of IL-10R-STAT3 signaling correlated with increased frequen

119 itro experiments confirmed reconstitution of IL-10R-mediated signaling in all patients who received t

120 require the two membrane-distal tyrosines of IL-10R, but Stat3 appears to function only in the anti-p

121 This process is dependent on IL-10R-mediated STAT3 signaling, as supported by the lac

122 ach, we identified 16 patients with IL-10 or IL-10R deficiency: 3 patients had mutations in IL-10, 5

123 genetic deletion of NK cell-derived IL-10 or IL-10R expression on T cells prevents IL-15C-induced Tfh

124 nhibit EAE in mice with a disrupted IL-10 or IL-10R gene.

125 pendent and was abrogated by Abs to IL-10 or IL-10R.

126 Blockade of TNF, IL-6, or IL-10R function with monoclonal antibodies reduced lung

127 the binding of Jak1 to IFN-alpha R beta L or IL-10R alpha.

128 crease in survival in IL-10 knockout mice or IL-10R-blocked B6 mice after IL-12 plus IL-18 treatment.

129 as preformed to identify the IL-10 receptor (IL-10R) and phosphorylated or nonphosphorylated Akt and

130 models, addition of interleukin-10 receptor (IL-10R) blockade to cytotoxic therapy modestly affected

131 rmining the structure of the IL-10 receptor (IL-10R) complex by cryo-electron microscopy at a resolut

132 c interleukin-10 (IL-10) and IL-10 receptor (IL-10R) deficiencies cause very early onset severe infla

133 erved internalization of the IL-10 receptor (IL-10R) in mucosal lymphocytes, which could limit cellul

134 ted deficiencies of IL-10 or IL-10 receptor (IL-10R) lead to immune dysregulation with life-threateni

135 mal mice, anti-interleukin (IL)-10 receptor (IL-10R) monoclonal antibody (MAb) treatment induced intr

136 blockade in vitro with anti-IL-10 receptor (IL-10R) monoclonal antibody restored LPMC IFN-gamma and

137 cobacter hepaticus plus anti-IL-10 receptor (IL-10R) monoclonal antibody was exacerbated by co-admini

138 Interleukin-10 receptor (IL-10R) signaling is considered to be a vital component

139 Intact interleukin-10 receptor (IL-10R) signaling on effector and T regulatory (Treg) ce

140 and therapeutic blockade of IL-10 receptor (IL-10R) was equivalent to CSF-1 neutralization in enhanc

141 In vivo blockade of the IL-10 receptor (IL-10R) with a neutralizing antibody resulted in rapid r

142 Blockade of IL-10 receptor (IL-10R) with an antagonist antibody dramatically reduced

143 ed IL-10R1, a subunit of the IL-10 receptor (IL-10R), and also SOCS3, a negative regulator of proinfl

144 back mechanism involving the IL-10 receptor (IL-10R).

145 DC-specific deletion of the IL-10 receptor (IL-10R).

146 was absent or overexpressed or its receptor (IL-10R) was blockaded.

147 ely 1000-fold lower affinity for recombinant IL-10R than does hIL-10, yet stimulates proliferation of

148 Consistent with previous reports, IL-10R blockade led to severe, fatal tissue destruction

149 soluble TNFR:Fc fusion protein, and soluble IL-10R were used.

150 al TG-resident CD8(+) T cells, but also that IL-10R blockade might have therapeutic potential to redu

151 ansduction through the IL-10R on AM and that IL-10R function can be inhibited by stimulation of Toll-

152 expressing interferon gamma, suggesting that IL-10R signaling limits effector T cell differentiation.

153 The IL-10R, together with reporter gene constructs containin

154 ion of the inhibitory cytokine IL-10 and the IL-10R are sustained after induction of LPS tolerance.

155 IL-22 does not bind the IL-10R.

156 ide insight into cytokine recognition by the IL-10R family and highlight the plasticity of type III i

157 ated in hepatoma cells stably expressing the IL-10R.

158 Together, these studies identify the IL-10R on VTA dopamine neurons as a potential regulator

159 sion of CXCL9 and -16 failed to occur if the IL-10R was blocked in vivo, an intervention associated w

160 6)) located in the cytoplasmic domain of the IL-10R alpha chain were required for receptor function,

161 show that antibody-mediated blockade of the IL-10R during P. berghei ANKA infection in ECM-resistant

162 The signaling capabilities of the IL-10R for activating specific STAT proteins and inducin

163 STAT proteins, confirmed a preference of the IL-10R for STAT3 and STAT1.

164 Surface expression of the IL-10R is transiently up-regulated on CD8 T cells follow

165 ing involves tyrosine phosphorylation of the IL-10R JAK1 (Janus kinase) and TYK2 (tyrosine kinase) re

166 r results revealed an unexpected role of the IL-10R pathway in lymphomagenesis.

167 These data establish that activation of the IL-10R promotes survival of progenitor myeloid cells.

168 environment, we found that expression of the IL-10R was required only on CD8(+) T cells to facilitate

169 nfection of IL-10(-/-) mice, blockade of the IL-10R, or depletion of CD25(+) cells during the chronic

170 pendent of C-terminal serine residues of the IL-10R, previously shown to be required for other anti-i

171 ate their signals via the STAT3 pathway, the IL-10R appears unique in promoting a potent anti-inflamm

172 Unlike many hematopoietin receptors, the IL-10R did not detectably activate STAT5.

173 The data demonstrate that the IL-10R, unlike other members of the interferon receptor

174 ulatory T cells and on signaling through the IL-10R and correlated with global downregulation of DC i

175 , stimulates signal transduction through the IL-10R on AM and that IL-10R function can be inhibited b

176 ation of a 110-kDa protein with an Ab to the IL-10R and by the ability of IL-10 to activate Jak1 and

177 ect was inhibited by neutralizing Abs to the IL-10R.

178 way dependent on STAT3 but not unique to the IL-10R.

179 To determine whether the IL-10R has signaling functions similar to IL-6R in cells

180 Coinjection of nt-nls-MmGFP with the IL-10R Tyr(446) and Tyr(496) amino-acid residues complet

181 Therapeutic IL-10R blockade broke the cycle of IL-10-mediated immune

182 When mAb to TGFbeta1 or to IL-10R was administered at the time of challenge, the re

183 Also, unlike IL-10R blockade, ICOSL blockade led to an expansion of b

184 nts with IL-10 deficiency and 1 patient with IL-10R alpha chain deficiency and proved to be an effect

185 induce sustained remission in 1 patient with IL-10R deficiency.

186 the lack of an IL-10 effect in patients with IL-10R deficiency and dominant-negative STAT3 mutation.

187 neic HSCT can induce remission in those with IL-10R deficiency.