Objective To study the expression of interleukin-2(IL-2), soluble interleukin-2 receptor (sIL-2R), determine the alteration of erythrocytic immunity and T cell subgroup in the blood of outer circulation in patients wi...Objective To study the expression of interleukin-2(IL-2), soluble interleukin-2 receptor (sIL-2R), determine the alteration of erythrocytic immunity and T cell subgroup in the blood of outer circulation in patients with hypertensive cerebral hemorrhage so and to probe into the relationship between them, and to explore the clinical significance. Methods Enzyme linked immnunosorbent assay (ELISA) was used to determine the content of IL-2 and sIL-2R. The immunoadsorption was employed to examine the erythrocytic immune activity and its regulating function. Streptavidin-peroxidase(S-P) was used to determine the cell number of CD3 (cluster of differentiation3), CD4 and CD8. Results The content of IL-2 in the group with hypertensive cerebral hemorrhage was significantly lower than that in the control group (P<0.01), and the content of sIL-2R increased. Red blood cell C_ 3b receptor (RBC.C_ 3b R) and RBC immune adherence enhancing factor (RFEB) dropped greatly (P<0.01), while RBC immune complex rosette (RBC.ICR) and RBC immune adherence inhibiting factor (RFIR) increased greatly. The cell number of CD3 and CD4decreased (P<0.01) and there was no obvious change in CD8 (P<0.05). Conclusion The decrease of immune function was observed in patients with hypertensive cerebral hemorrhage. The determination of the content of IL-2, sIL-2R, erythrocytic immunity and the activity of T subgroup has an important clinical significance in the occurrence, development, treatment, and prognosis of hypertensive cerebral hemorrhage.展开更多
Interleukin-2(IL-2)is an important cytokine that plays a key role in the immune response.The IL-2 receptor(IL-2R)is composed of three subunits,alpha,beta,and gamma,with the alpha subunit having the highest affinity fo...Interleukin-2(IL-2)is an important cytokine that plays a key role in the immune response.The IL-2 receptor(IL-2R)is composed of three subunits,alpha,beta,and gamma,with the alpha subunit having the highest affinity for IL-2.Several studies reported that immune dysregulation of IL-2 may cause tissue injury as well as damage leading to the pathogenesis of various autoimmune diseases such as acute necrotizing vasculitis in systemic lupus erythematosus(SLE),inflammatory synovitis in rheumatoid arthritis(RA),salivary and lacrimal gland dysfunction in Sjogren syndrome(SS),obliterative vasculopathy fibrosis in systemic sclerosis(SSc),and inflammatory demyelination in multiple sclerosis(MS).The aim of this review paper was to examine the role of IL-2/IL-2R in various autoimmune disorders,taking into account recent advancements and discoveries,gaps in the current literature,ongoing debates,and potential avenues for future research.The focus of this review is on systemic lupus erythematosus,rheumatoid arthritis,systemic sclerosis,sjogren syndrome,and multiple sclerosis,which are all linked to the malfunctioning of IL-2/IL-2R.In genetic studies,gene polymorphisms of IL-2 such as IL-2330/T,IL-2330/G,and rs2069763 are involved in increasing the risk of SLE.Furthermore,genetic associations of IL-2/IL-2R such as rs791588,rs2281089,rs2104286,rs11594656,and rs35285258 are significantly associated with RA susceptibility.The IL-2 polymorphism including rs2069762A,rs6822844T,rs6835457G,and rs907715T are significant connections with systemic sclerosis.In addition,rs2104286(IL-2),rs11594656(IL-2RA),rs35285258(IL-2RB)gene polymorphism significant increases the risk of multiple sclerosis.In therapeutic approaches,low-dose IL-2 therapy could regulate Tfr and Tfh cells,resulting in a reduction in disease activity in the SLE patients.In addition,elevated sIL-2R levels in the peripheral blood of SLE patients could be linked to an immunoregulatory imbalance,which may contribute to the onset and progression of SLE.Consequently,sIL-2R could potentially be a target for future SLE therapy.Moreover,Low dose-IL2 was well-tolerated,and low levels of Treg and high levels of IL-21 wereassociated with positive responses to Ld-IL2 suggested to be a safe and effective treatment for RA.Additionally,low-dose IL-2 treatment improves the exocrine glands'ability to secrete saliva in SS-affected mice.Whereas,Basiliximab targets the alpha chain of the IL-2 receptor suggested as a potential treatment for SSc.Also,pre-andpost-treatment with Tregs,MDSCs,and IL-2 may have the potential to prevent EAE induction in patients with MS.It is suggested that further studies should be conducted on IL-2 polymorphism in Sjogren syndrome.展开更多
Signaling via interleukin-2 receptor(IL-2R)is a requisite for regulatory T(Treg)cell identity and function.However,it is not completely understood to what degree IL-2R signaling is required for Treg cell homeostasis,l...Signaling via interleukin-2 receptor(IL-2R)is a requisite for regulatory T(Treg)cell identity and function.However,it is not completely understood to what degree IL-2R signaling is required for Treg cell homeostasis,lineage stability and function in both resting and inflammatory conditions.Here,we characterized a spontaneous mutant mouse strain endowed with a hypomorphic Tyr129His variant of CD25,theα-chain of IL-2R,which resulted in diminished receptor expression and reduced IL-2R signaling.Under noninflammatory conditions,Cd25Y129H mice harbored substantially lower numbers of peripheral Treg cells with stable Foxp3 expression that prevented the development of spontaneous autoimmune disease.In contrast,Cd25^(Y^(129H))Treg cells failed to efficiently induce immune suppression and lost lineage commitment in a T-cell transfer colitis model,indicating that unimpaired IL-2R signaling is critical for Treg cell function in inflammatory environments.Moreover,single-cell RNA sequencing of Treg cells revealed that impaired IL-2R signaling profoundly affected the balance of central and effector Treg cell subsets.Thus,partial loss of IL-2R signaling differentially interferes with the maintenance,heterogeneity,and suppressive function of the Treg cell pool.展开更多
Both interleukin-2 (IL-2) receptor y subunit and non-receptor tyrosine kinase Jak3 play important roles in IL-2 physiological functions. Jak3 has been known to bind IL-2Ry and the interaction is very important for IL-...Both interleukin-2 (IL-2) receptor y subunit and non-receptor tyrosine kinase Jak3 play important roles in IL-2 physiological functions. Jak3 has been known to bind IL-2Ry and the interaction is very important for IL-2 signaling. In order to find the domains directly involved in the interaction between IL-2Ry and Jak3, various deletion mutants have been constructed展开更多
The 126Gln of human interleukin-2 (IL-2) is a conserved amino acid residue. After substitution of 126Gln with Asp, the binding abilities of this mutant to different composites of IL-2 receptor (R) subunits have been d...The 126Gln of human interleukin-2 (IL-2) is a conserved amino acid residue. After substitution of 126Gln with Asp, the binding abilities of this mutant to different composites of IL-2 receptor (R) subunits have been determined. Results show that 126Asp-IL-2 has higher affinity to IL-2R α βγ complex and normal affinity to IL-2R α β complex, but loses its binding ability to IL-2R β γ complex, demonstrating that the 126Gln is the residue of human IL-2 which binds to IL-2R 7 subunit.展开更多
Purinergic signaling plays a causal role in the modulation of immune inflammatory response in the course of psoriasis,but its regulatory mechanism remains unclear.As a member of purinoceptors,P2Y_(6)R mainly distribut...Purinergic signaling plays a causal role in the modulation of immune inflammatory response in the course of psoriasis,but its regulatory mechanism remains unclear.As a member of purinoceptors,P2Y_(6)R mainly distributed in macrophages was significantly up-expressed in skin lesions from patients with psoriasis in the present study.Here,the severity of psoriasis was alleviated in imiquimod-treated mice with macrophages conditional knockout of P2Y_(6)R,while the cell-chat algorithm showed there was a correlation between macrophage P2Y_(6)R and Th1 cells mediated by IL-27.Mechanistically,P2Y_(6)R enhanced PLCβ/p-PKC/MAPK activation to induce IL-27 release dependently,which subsequently regulated the differentiation of Th1 cells,leading to erythematous and scaly plaques of psoriasis.Interestingly,we developed a novel P2Y_(6)R inhibitor FS-6,which bonds with the ARG266 side chain of P2Y_(6)R,exhibited remarkable anti-psoriasis effects targeting P2Y_(6)R.Our study provides insights into the role of P2Y_(6)R in the pathogenesis of psoriasis and suggests its potential as a target for the development of therapeutic interventions.A novel P2Y_(6)R inhibitor FS-6 could be developed as an anti-psoriasis drug candidate for the clinic.展开更多
文摘Objective To study the expression of interleukin-2(IL-2), soluble interleukin-2 receptor (sIL-2R), determine the alteration of erythrocytic immunity and T cell subgroup in the blood of outer circulation in patients with hypertensive cerebral hemorrhage so and to probe into the relationship between them, and to explore the clinical significance. Methods Enzyme linked immnunosorbent assay (ELISA) was used to determine the content of IL-2 and sIL-2R. The immunoadsorption was employed to examine the erythrocytic immune activity and its regulating function. Streptavidin-peroxidase(S-P) was used to determine the cell number of CD3 (cluster of differentiation3), CD4 and CD8. Results The content of IL-2 in the group with hypertensive cerebral hemorrhage was significantly lower than that in the control group (P<0.01), and the content of sIL-2R increased. Red blood cell C_ 3b receptor (RBC.C_ 3b R) and RBC immune adherence enhancing factor (RFEB) dropped greatly (P<0.01), while RBC immune complex rosette (RBC.ICR) and RBC immune adherence inhibiting factor (RFIR) increased greatly. The cell number of CD3 and CD4decreased (P<0.01) and there was no obvious change in CD8 (P<0.05). Conclusion The decrease of immune function was observed in patients with hypertensive cerebral hemorrhage. The determination of the content of IL-2, sIL-2R, erythrocytic immunity and the activity of T subgroup has an important clinical significance in the occurrence, development, treatment, and prognosis of hypertensive cerebral hemorrhage.
文摘Interleukin-2(IL-2)is an important cytokine that plays a key role in the immune response.The IL-2 receptor(IL-2R)is composed of three subunits,alpha,beta,and gamma,with the alpha subunit having the highest affinity for IL-2.Several studies reported that immune dysregulation of IL-2 may cause tissue injury as well as damage leading to the pathogenesis of various autoimmune diseases such as acute necrotizing vasculitis in systemic lupus erythematosus(SLE),inflammatory synovitis in rheumatoid arthritis(RA),salivary and lacrimal gland dysfunction in Sjogren syndrome(SS),obliterative vasculopathy fibrosis in systemic sclerosis(SSc),and inflammatory demyelination in multiple sclerosis(MS).The aim of this review paper was to examine the role of IL-2/IL-2R in various autoimmune disorders,taking into account recent advancements and discoveries,gaps in the current literature,ongoing debates,and potential avenues for future research.The focus of this review is on systemic lupus erythematosus,rheumatoid arthritis,systemic sclerosis,sjogren syndrome,and multiple sclerosis,which are all linked to the malfunctioning of IL-2/IL-2R.In genetic studies,gene polymorphisms of IL-2 such as IL-2330/T,IL-2330/G,and rs2069763 are involved in increasing the risk of SLE.Furthermore,genetic associations of IL-2/IL-2R such as rs791588,rs2281089,rs2104286,rs11594656,and rs35285258 are significantly associated with RA susceptibility.The IL-2 polymorphism including rs2069762A,rs6822844T,rs6835457G,and rs907715T are significant connections with systemic sclerosis.In addition,rs2104286(IL-2),rs11594656(IL-2RA),rs35285258(IL-2RB)gene polymorphism significant increases the risk of multiple sclerosis.In therapeutic approaches,low-dose IL-2 therapy could regulate Tfr and Tfh cells,resulting in a reduction in disease activity in the SLE patients.In addition,elevated sIL-2R levels in the peripheral blood of SLE patients could be linked to an immunoregulatory imbalance,which may contribute to the onset and progression of SLE.Consequently,sIL-2R could potentially be a target for future SLE therapy.Moreover,Low dose-IL2 was well-tolerated,and low levels of Treg and high levels of IL-21 wereassociated with positive responses to Ld-IL2 suggested to be a safe and effective treatment for RA.Additionally,low-dose IL-2 treatment improves the exocrine glands'ability to secrete saliva in SS-affected mice.Whereas,Basiliximab targets the alpha chain of the IL-2 receptor suggested as a potential treatment for SSc.Also,pre-andpost-treatment with Tregs,MDSCs,and IL-2 may have the potential to prevent EAE induction in patients with MS.It is suggested that further studies should be conducted on IL-2 polymorphism in Sjogren syndrome.
基金This work was supported by the ERC Advanced Grants 322645,SFB900-B1,and SFB738-B5(all to R.F.)and SFB738-C7(to J.H.).We gratefully acknowledge the assistance of Dr.Matthias Ballmaier of the Cell Sorting Core Facility of Hannover Medical School for superb service.The cDNA and HTO libraries used in this publication were sequenced at the Research Core Unit Genomics at Hannover Medical School.We thank Svetlana Piter for providing excellent animal care and Natalio Garbi(IEI Bonn)for providing Ccr2^(−/−)(Ccr2^(tm1Mae))mice.
文摘Signaling via interleukin-2 receptor(IL-2R)is a requisite for regulatory T(Treg)cell identity and function.However,it is not completely understood to what degree IL-2R signaling is required for Treg cell homeostasis,lineage stability and function in both resting and inflammatory conditions.Here,we characterized a spontaneous mutant mouse strain endowed with a hypomorphic Tyr129His variant of CD25,theα-chain of IL-2R,which resulted in diminished receptor expression and reduced IL-2R signaling.Under noninflammatory conditions,Cd25Y129H mice harbored substantially lower numbers of peripheral Treg cells with stable Foxp3 expression that prevented the development of spontaneous autoimmune disease.In contrast,Cd25^(Y^(129H))Treg cells failed to efficiently induce immune suppression and lost lineage commitment in a T-cell transfer colitis model,indicating that unimpaired IL-2R signaling is critical for Treg cell function in inflammatory environments.Moreover,single-cell RNA sequencing of Treg cells revealed that impaired IL-2R signaling profoundly affected the balance of central and effector Treg cell subsets.Thus,partial loss of IL-2R signaling differentially interferes with the maintenance,heterogeneity,and suppressive function of the Treg cell pool.
文摘Both interleukin-2 (IL-2) receptor y subunit and non-receptor tyrosine kinase Jak3 play important roles in IL-2 physiological functions. Jak3 has been known to bind IL-2Ry and the interaction is very important for IL-2 signaling. In order to find the domains directly involved in the interaction between IL-2Ry and Jak3, various deletion mutants have been constructed
基金Project supported by the "863" Project of China.
文摘The 126Gln of human interleukin-2 (IL-2) is a conserved amino acid residue. After substitution of 126Gln with Asp, the binding abilities of this mutant to different composites of IL-2 receptor (R) subunits have been determined. Results show that 126Asp-IL-2 has higher affinity to IL-2R α βγ complex and normal affinity to IL-2R α β complex, but loses its binding ability to IL-2R β γ complex, demonstrating that the 126Gln is the residue of human IL-2 which binds to IL-2R 7 subunit.
基金supported by the funds from National Natural Science Foundation of China(No.82304506,No.82373887,No.82373725)the China Postdoctoral Science Foundation(2022M723513,China).
文摘Purinergic signaling plays a causal role in the modulation of immune inflammatory response in the course of psoriasis,but its regulatory mechanism remains unclear.As a member of purinoceptors,P2Y_(6)R mainly distributed in macrophages was significantly up-expressed in skin lesions from patients with psoriasis in the present study.Here,the severity of psoriasis was alleviated in imiquimod-treated mice with macrophages conditional knockout of P2Y_(6)R,while the cell-chat algorithm showed there was a correlation between macrophage P2Y_(6)R and Th1 cells mediated by IL-27.Mechanistically,P2Y_(6)R enhanced PLCβ/p-PKC/MAPK activation to induce IL-27 release dependently,which subsequently regulated the differentiation of Th1 cells,leading to erythematous and scaly plaques of psoriasis.Interestingly,we developed a novel P2Y_(6)R inhibitor FS-6,which bonds with the ARG266 side chain of P2Y_(6)R,exhibited remarkable anti-psoriasis effects targeting P2Y_(6)R.Our study provides insights into the role of P2Y_(6)R in the pathogenesis of psoriasis and suggests its potential as a target for the development of therapeutic interventions.A novel P2Y_(6)R inhibitor FS-6 could be developed as an anti-psoriasis drug candidate for the clinic.
