B-cell expression of IL-21R notably exceeds that of
T cells. A large number of studies confirm that IL-21 involved in
the regulation of both B cell proliferation and maturation. IL-21
can stimulate B cells proliferation and differentiation in the
context of a co-stimulatory T-cell signal. IL-21-mediated human
B-cell differentiation requires signal transducer and activator of
transcription 3 (STAT3), and cannot be compensated by alternative
signaling pathways (25). The effect
of IL-21 can be augmented by IL-2 or IL-10, and IL-21 induces IL-10
in human B cells and interacts with TGF-β (26,27). In
particular, IL-21 promotes B cells differentiation to Ig-producing
plasma through its induction of B lymphocyte-induced maturation
protein-1 (28), which is a
transcription factor critical for plasma cell formation. Notably,
IL-21 also induces B cell apoptosis either in the absence of a
T-cell signal or in the activation of a Toll-like receptor signal
(29). The pro-apoptotic activity of
IL-21 results from the induction of BCL-2, which is a pro-apoptotic
protein.
IL-21 has broad actions on T and B cells, but its
innate immunity is poorly understood. IL-21 has a potent inhibitory
effect on granulocyte-macrophage colony-stimulating factor
(GM-CSF)-induced dendritic cells (DCs) (30). IL-21 induces apoptosis of conventional
DCs (cDCs) via STAT3 and inhibiting Bim, and this effect is
prevented by GM-CSF, which partially opposes the biological action
by these cytokines. Furthermore, the number of STAT3 sites was
reduced in the presence of GM-CSF when DCs were treated with IL-21,
and GM-CSF primarily activates STAT5 instead of STAT3 and inhibits
Bim (31). These findings suggest that
IL-21-induced STAT3-dependent apoptosis of DCs provides a mechanism
for alleviating the immune response, and IL-21 has a cross-negative
regulation with GM-CSF.
IL-21 regulates the innate and adaptive immune
responses via heterodimers of the IL-21R and the common cytokine
receptor γc1. IL-21 signals via the Janus kinase (JAK)-STAT
signaling pathway (25,26), the mitogen-activated protein kinase
signaling pathway and the phosphoinositide 3-kinase-AKT signaling
pathway (2). Of these, the JAK-STAT
pathway has been the most extensively studied. In T cells, IL-21
activates STAT3 more than STAT1 and STAT5. STAT1 and STAT3 have
partially opposing roles in IL-21 signaling. RNA-sequence analysis
showed that STAT1 and STAT3 are critical for IL-21-mediated gene
regulation, including Tbx21 and interferon γ (32). Notably, IL-21-induced expression of
suppressor of cytokine signaling 3 (Socs3) and Socs1 are decreased
in Stat3−/− cells (33).
SOCS3 and SOCS1 can negatively regulate STAT protein
phosphorylation, and this may in part explain the opposing roles of
STAT1 and STAT3 in IL-21 function in CD4+ T cells. In
cDCs, IL-21 induces IL-1β production via a STAT3 dependent and
nuclear factor-κB independent pathway. Furthermore, this processing
in cDCs does not require caspase-1 or caspase-8, but depends on
IL-21-mediated death (34). IL-21 can
induce the expression of PR domain containing 1, with ZNF domain in
multiple B lymphoma cell lines, and IL-21 induces STAT3 binding
also bound interferon regulatory factor 4 (IRF4) in vivo
(35,36), and Irf4−/− mice showed
impaired IL-21 induced Tfh cells differentiation (37). These results reveal broad cooperative
gene regulation by STAT3 and IRF4. In T cells, numerous target
genes of IL-21 are regulated through basic leucine zipper
transcription factor, ATF-like, JUN, IRF4 and STAT3 (37,38).
Notably, these transcription factors are also potential targets
through which IL-21 signaling may be regulated. Our recent study
reported that IL-21 activated STAT3 in HUVECs exposed to ischemia
conditions; however, there were no significant changes in STAT1,
AKT1 or extracellular-signal-regulated kinase 1/2 (ERK1/2)
phosphorylation at any time point following IL-21 treatment
(9).
It has been shown that IL-21R exists in endothelial
cells (ECs), which is a key process in the formation of new blood
vessels during angiogenesis. IL-21 treatment decreases EC
proliferation and sprouting in vitro. Furthermore, in a
tumor mouse model, IL-21 inhibited tumor angiogenesis in
vivo and decreased angiogenesis vascular endothelial growth
factor A and its receptors (10).
Another study demonstrated conflicting results, in which genetic
ablation of IL-21 in Apcmin/+ mice reduced STAT3
activation and diminished cytokines, including IL-6 and tumor
necrosis factor-α, and decreased angiogenesis in the lesions
(8).
In our recent study of a mouse model with surgical
hindlimb ischemia (HLI), the IL-21R levels were higher in the
EC-enriched fraction isolated from ischemic hindlimb muscle.
Furthermore, HUVECs showed 10-fold IL-21R expression following
hypoxia and serum starvation in vitro. IL-21 treatment
increased cell viability, decreased cell apoptosis and augmented
tube formation in HUVECs under ischemic conditions. Knockout IL-21R
resulted in less perfusion recovery following HLI in vivo.
In particular, the activated STAT3 pathway and increase in the
BCL-2/BCL-2-associated X protein ratio were involved in the in
vitro and in vivo experiments (9). These results suggest that the elevated
IL-21R levels in EC in ischemia muscle are adaptive.
Numerous studies have shown that IL-21 has
therapeutic effects in animal models of a wide range of diseases
[including cancer (12),
immunity-deficient disease (39), type
1 diabetes (40) and inflammatory
bowel disease (41)] and various
clinical trials are underway (42).
An investigation regarding the association between
IL-21 levels and myocardial function following acute myocardial
showed that plasma IL-21 concentration correlated significantly
with left ventricular end-systolic volume index, and multivariate
analysis suggested that IL-21 was an independent predictor of
remodeling. Furthermore, IL-21 was also significantly associated
with higher tissue inhibitor of metalloproteinases-4 (TIMP-4)
concentrations and lower MMP-9 concentrations (43). A previous experiment demonstrated that
IL-21R was expressed on cardiac fibroblasts (44), and whether IL-21 may directly stimulate
MMP/TIMP release within the myocardium is unknown and merits
further study.
IL-21 has been implicated in broad immunological
processes since its discovery in 2000. IL-21 regulates at least 3
pathways (STAT3, ERK1/2 and AKT-1), which can either enhance cell
survival or pro-apoptosis in different cell lines. IL-21 signaling
pathways are complex due to their cooperation with other
transcriptional factors. With the improvement of our understanding
in IL-21 biology regarding each specific disease or pathological
condition, IL-21 could be a new therapeutic target for immune
relative disease.
The present study was partially supported by
National Natural Science Foundation of China (grant no.
81300315)
|
1.
|
Parrish-Novak J, Dillon SR, Nelson A,
Hammond A, Sprecher C, Gross JA, Johnston J, Madden K, Xu W, West
J, et al: Interleukin 21 and its receptor are involved in NK cell
expansion and regulation of lymphocyte function. Nature. 408:57–63.
2000. View
Article : Google Scholar : PubMed/NCBI
|
|
2.
|
Spolski R and Leonard WJ: Interleukin-21:
A double-edged sword with therapeutic potential. Nat Rev Drug
Discov. 13:379–395. 2014. View
Article : Google Scholar : PubMed/NCBI
|
|
3.
|
Mehta DS, Wurster AL and Grusby MJ:
Biology of IL-21 and the IL-21 receptor. Immunol Rev. 202:84–95.
2004. View Article : Google Scholar : PubMed/NCBI
|
|
4.
|
Ozaki K, Kikly K, Michalovich D, Young PR
and Leonard WJ: Cloning of a type I cytokine receptor most related
to the IL-2 receptor beta chain. Proc Natl Acad Sci USA.
97:11439–11444. 2000. View Article : Google Scholar : PubMed/NCBI
|
|
5.
|
Asao H, Okuyama C, Kumaki S, Ishii N,
Tsuchiya S, Foster D and Sugamura K: Cutting edge: The common
gamma-chain is an indispensable subunit of the IL-21 receptor
complex. J Immunol. 167:1–5. 2001. View Article : Google Scholar : PubMed/NCBI
|
|
6.
|
Spolski R and Leonard WJ: Interleukin-21:
Basic biology and implications for cancer and autoimmunity. Annu
Rev Immunol. 26:57–79. 2008. View Article : Google Scholar : PubMed/NCBI
|
|
7.
|
Vogelzang A, McGuire HM, Liu SM, Gloss B,
Mercado K, Earls P, Dinger ME, Batten M, Sprent J and King C: IL-21
contributes to fatal inflammatory disease in the absence of
Foxp3+ T regulatory cells. J Immunol. 192:1404–1414.
2014. View Article : Google Scholar : PubMed/NCBI
|
|
8.
|
De Simone V, Ronchetti G, Franzè E,
Colantoni A, Ortenzi A, Fantini MC, Rizzo A, Sica GS, Sileri P,
Rossi P, et al: Interleukin-21 sustains inflammatory signals that
contribute to sporadic colon tumorigenesis. Oncotarget.
6:9908–9923. 2015. View Article : Google Scholar : PubMed/NCBI
|
|
9.
|
Kanada M, Bachmann MH, Hardy JW,
Frimannson DO, Bronsart L, Wang A, Sylvester MD, Schmidt TL, Kaspar
RL, Butte MJ, et al: Differential fates of biomolecules delivered
to target cells via extracellular vesicles. Proc Natl Acad Sci USA.
112:E1433–E1442. 2015.PubMed/NCBI
|
|
10.
|
Castermans K, Tabruyn SP, Zeng R, van
Beijnum JR, Eppolito C, Leonard WJ, Shrikant PA and Griffioen AW:
Angiostatic activity of the antitumor cytokine interleukin-21.
Blood. 112:4940–4947. 2008. View Article : Google Scholar : PubMed/NCBI
|
|
11.
|
Leonard WJ and Spolski R: Interleukin-21:
A modulator of lymphoid proliferation, apoptosis and
differentiation. Nat Rev Immunol. 5:688–698. 2005. View Article : Google Scholar : PubMed/NCBI
|
|
12.
|
Davis MR, Zhu Z, Hansen DM, Bai Q and Fang
Y: The role of IL-21 in immunity and cancer. Cancer Lett.
358:107–114. 2015. View Article : Google Scholar : PubMed/NCBI
|
|
13.
|
Pesce J, Kaviratne M, Ramalingam TR,
Thompson RW, Urban JF Jr, Cheever AW, Young DA, Collins M, Grusby
MJ and Wynn TA: The IL-21 receptor augments Th2 effector function
and alternative macrophage activation. J Clin Invest.
116:2044–2055. 2006. View
Article : Google Scholar : PubMed/NCBI
|
|
14.
|
Fröhlich A, Marsland BJ, Sonderegger I,
Kurrer M, Hodge MR, Harris NL and Kopf M: IL-21 receptor signaling
is integral to the development of Th2 effector responses in vivo.
Blood. 109:2023–2031. 2007. View Article : Google Scholar : PubMed/NCBI
|
|
15.
|
Zhou L, Ivanov II, Spolski R, Min R,
Shenderov K, Egawa T, Levy DE, Leonard WJ and Littman DR: IL-6
programs T(H)-17 cell differentiation by promoting sequential
engagement of the IL-21 and IL-23 pathways. Nat Immunol. 8:967–974.
2007. View
Article : Google Scholar : PubMed/NCBI
|
|
16.
|
Nurieva R, Yang XO, Martinez G, Zhang Y,
Panopoulos AD, Ma L, Schluns K, Tian Q, Watowich SS, Jetten AM, et
al: Essential autocrine regulation by IL-21 in the generation of
inflammatory T cells. Nature. 448:480–483. 2007. View Article : Google Scholar : PubMed/NCBI
|
|
17.
|
Nurieva RI, Chung Y, Hwang D, Yang XO,
Kang HS, Ma L, Wang YH, Watowich SS, Jetten AM, Tian Q, et al:
Generation of T follicular helper cells is mediated by
interleukin-21 but independent of T helper 1, 2, or 17 cell
lineages. Immunity. 29:138–149. 2008. View Article : Google Scholar : PubMed/NCBI
|
|
18.
|
Eto D, Lao C, DiToro D, Barnett B, Escobar
TC, Kageyama R, Yusuf I and Crotty S: IL-21 and IL-6 are critical
for different aspects of B cell immunity and redundantly induce
optimal follicular helper CD4 T cell (Tfh) differentiation. PLoS
One. 6:e177392011. View Article : Google Scholar : PubMed/NCBI
|
|
19.
|
Karnowski A, Chevrier S, Belz GT, Mount A,
Emslie D, D'Costa K, Tarlinton DM, Kallies A and Corcoran LM: B and
T cells collaborate in antiviral responses via IL-6, IL-21, and
transcriptional activator and coactivator, Oct2 and OBF-1. J Exp
Med. 209:2049–2064. 2012. View Article : Google Scholar : PubMed/NCBI
|
|
20.
|
Kastirr I, Maglie S, Paroni M, Alfen JS,
Nizzoli G, Sugliano E, Crosti MC, Moro M, Steckel B, Steinfelder S,
et al: IL-21 is a central memory T cell-associated cytokine that
inhibits the generation of pathogenic Th1/17 effector cells. J
Immunol. 193:3322–3331. 2014. View Article : Google Scholar : PubMed/NCBI
|
|
21.
|
Bauquet AT, Jin H, Paterson AM,
Mitsdoerffer M, Ho IC, Sharpe AH and Kuchroo VK: The costimulatory
molecule ICOS regulates the expression of c-Maf and IL-21 in the
development of follicular T helper cells and TH-17 cells. Nat
Immunol. 10:167–175. 2009. View
Article : Google Scholar : PubMed/NCBI
|
|
22.
|
Nurieva RI, Chung Y, Martinez GJ, Yang XO,
Tanaka S, Matskevitch TD, Wang YH and Dong C: Bcl6 mediates the
development of T follicular helper cells. Science. 325:1001–1005.
2009. View Article : Google Scholar : PubMed/NCBI
|
|
23.
|
Korn T, Bettelli E, Gao W, Awasthi A,
Jäger A, Strom TB, Oukka M and Kuchroo VK: IL-21 initiates an
alternative pathway to induce proinflammatory T(H)17 cells. Nature.
448:484–487. 2007. View Article : Google Scholar : PubMed/NCBI
|
|
24.
|
Attridge K, Wang CJ, Wardzinski L,
Kenefeck R, Chamberlain JL, Manzotti C, Kopf M and Walker LS: IL-21
inhibits T cell IL-2 production and impairs Treg homeostasis.
Blood. 119:4656–4664. 2012. View Article : Google Scholar : PubMed/NCBI
|
|
25.
|
Berglund LJ, Avery DT, Ma CS, Moens L,
Deenick EK, Bustamante J, Boisson-Dupuis S, Wong M, Adelstein S,
Arkwright PD, et al: IL-21 signalling via STAT3 primes human naive
B cells to respond to IL-2 to enhance their differentiation into
plasmablasts. Blood. 122:3940–3950. 2013. View Article : Google Scholar : PubMed/NCBI
|
|
26.
|
Deenick EK, Avery DT, Chan A, Berglund LJ,
Ives ML, Moens L, Stoddard JL, Bustamante J, Boisson-Dupuis S,
Tsumura M, et al: Naive and memory human B cells have distinct
requirements for STAT3 activation to differentiate into
antibody-secreting plasma cells. J Exp Med. 210:2739–2753. 2013.
View Article : Google Scholar : PubMed/NCBI
|
|
27.
|
Avery DT, Bryant VL, Ma CS, de Waal
Malefyt R and Tangye SG: IL-21-induced isotype switching to IgG and
IgA by human naive B cells is differentially regulated by IL-4. J
Immunol. 181:1767–1779. 2008. View Article : Google Scholar : PubMed/NCBI
|
|
28.
|
Ozaki K, Spolski R, Ettinger R, Kim HP,
Wang G, Qi CF, Hwu P, Shaffer DJ, Akilesh S, Roopenian DC, et al:
Regulation of B cell differentiation and plasma cell generation by
IL-21, a novel inducer of Blimp-1 and Bcl-6. J Immunol.
173:5361–5371. 2004. View Article : Google Scholar : PubMed/NCBI
|
|
29.
|
Liu BS, Stoop JN, Huizinga TW and Toes RE:
IL-21 enhances the activity of the TLR-MyD88-STAT3 pathway but not
the classical TLR-MyD88-NF-κB pathway in human B cells to boost
antibody production. J Immunol. 191:4086–4094. 2013. View Article : Google Scholar : PubMed/NCBI
|
|
30.
|
Brandt K, Bulfone-Paus S, Foster DC and
Rückert R: Interleukin-21 inhibits dendritic cell activation and
maturation. Blood. 102:4090–4098. 2003. View Article : Google Scholar : PubMed/NCBI
|
|
31.
|
Wan CK, Oh J, Li P, West EE, Wong EA,
Andraski AB, Spolski R, Yu ZX, He J, Kelsall BL, et al: The
cytokines IL-21 and GM-CSF have opposing regulatory roles in the
apoptosis of conventional dendritic cells. Immunity. 38:514–527.
2013. View Article : Google Scholar : PubMed/NCBI
|
|
32.
|
Wan CK, Andraski AB, Spolski R, Li P,
Kazemian M, Oh J, Samsel L, Swanson PA II, McGavern DB, Sampaio EP,
et al: Opposing roles of STAT1 and STAT3 in IL-21 function in
CD4+ T cells. Proc Natl Acad Sci USA. 112:9394–9399.
2015. View Article : Google Scholar : PubMed/NCBI
|
|
33.
|
Strengell M, Lehtonen A, Matikainen S and
Julkunen I: IL-21 enhances SOCS gene expression and inhibits
LPS-induced cytokine production in human monocyte-derived dendritic
cells. J Leukoc Biol. 79:1279–1285. 2006. View Article : Google Scholar : PubMed/NCBI
|
|
34.
|
Wan CK, Li P, Spolski R, Oh J, Andraski
AB, Du N, Yu ZX, Dillon CP, Green DR and Leonard WJ: IL-21-mediated
non-canonical pathway for IL-1β production in conventional
dendritic cells. Nat Commun. 6:79882015. View Article : Google Scholar : PubMed/NCBI
|
|
35.
|
Huber M, Brüstle A, Reinhard K, Guralnik
A, Walter G, Mahiny A, von Löw E and Lohoff M: IRF4 is essential
for IL-21-mediated induction, amplification, and stabilization of
the Th17 phenotype. Proc Natl Acad Sci USA. 105:20846–20851. 2008.
View Article : Google Scholar : PubMed/NCBI
|
|
36.
|
Kwon H, Thierry-Mieg D, Thierry-Mieg J,
Kim HP, Oh J, Tunyaplin C, Carotta S, Donovan CE, Goldman ML,
Tailor P, et al: Analysis of interleukin-21-induced Prdm1 gene
regulation reveals functional cooperation of STAT3 and IRF4
transcription factors. Immunity. 31:941–952. 2009. View Article : Google Scholar : PubMed/NCBI
|
|
37.
|
Li P, Spolski R, Liao W, Wang L, Murphy
TL, Murphy KM and Leonard WJ: BATF-JUN is critical for
IRF4-mediated transcription in T cells. Nature. 490:543–546. 2012.
View Article : Google Scholar : PubMed/NCBI
|
|
38.
|
Glasmacher E, Agrawal S, Chang AB, Murphy
TL, Zeng W, Van der Lugt B, Khan AA, Ciofani M, Spooner CJ, Rutz S,
et al: A genomic regulatory element that directs assembly and
function of immune-specific AP-1-IRF complexes. Science.
338:975–980. 2012. View Article : Google Scholar : PubMed/NCBI
|
|
39.
|
Kotlarz D, Ziętara N, Uzel G, Weidemann T,
Braun CJ, Diestelhorst J, Krawitz PM, Robinson PN, Hecht J,
Puchałka J, et al: Loss-of-function mutations in the IL-21 receptor
gene cause a primary immunodeficiency syndrome. J Exp Med.
210:433–443. 2013. View Article : Google Scholar : PubMed/NCBI
|
|
40.
|
Spolski R, Kashyap M, Robinson C, Yu Z and
Leonard WJ: IL-21 signaling is critical for the development of type
I diabetes in the NOD mouse. Proc Natl Acad Sci USA.
105:14028–14033. 2008. View Article : Google Scholar : PubMed/NCBI
|
|
41.
|
Salzer E, Kansu A, Sic H, Májek P,
Ikincioğullari A, Dogu FE, Prengemann NK, Santos-Valente E, Pickl
WF, Bilic I, et al: Early-onset inflammatory bowel disease and
common variable immunodeficiency-like disease caused by IL-21
deficiency. J Allergy Clin Immunol. 133:1651–1659.e12. 2014.
View Article : Google Scholar : PubMed/NCBI
|
|
42.
|
Tangye SG: Advances in IL-21
biology-enhancing our understanding of human disease. Curr Opin
Immunol. 34:107–115. 2015. View Article : Google Scholar : PubMed/NCBI
|
|
43.
|
Weir RA, Miller AM, Petrie CJ, Clements S,
Steedman T, Dargie HJ, Squire IB, Ng LL, McInnes IB and McMurray
JJ: Interleukin-21 - a biomarker of importance in predicting
myocardial function following acute infarction? Cytokine.
60:220–225. 2012. View Article : Google Scholar : PubMed/NCBI
|
|
44.
|
Monteleone G, Caruso R, Fina D, Peluso I,
Gioia V, Stolfi C, Fantini MC, Caprioli F, Tersigni R, Alessandroni
L, et al: Control of matrix metalloproteinase production in human
intestinal fibroblasts by interleukin 21. Gut. 55:1774–1780. 2006.
View Article : Google Scholar : PubMed/NCBI
|
