YCLIM-07286; No. of pages: 6; 4C: Clinical Immunology (2014) xx, xxx–xxx
available at www.sciencedirect.com
Clinical Immunology www.elsevier.com/locate/yclim
4
5Q1 6
7 8
Isao Matsumoto ⁎, Asuka Inoue, Chinatsu Takai, Naoto Umeda, Yuki Tanaka, Yuko Kurashima, Takayuki Sumida Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
D
9
Received 5 February 2014; 24 March 2014; accepted with revision 25 March 2014
E
10
Rheumatoid arthritis; TNFα; IL-6; TNFAIP3; TNFAIP9
16 17 18
Abstract Tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) have proved to be important in rheumatoid arthritis (RA) because the outcome of RA has greatly improved with the recent availability of biologics targeting them. It is well accepted that these cytokines are involved in the activation of the nuclear factor-κB (NF-κB) signaling pathway, but our understanding of the dependency of these pro-inflammatory cytokines and the link between them in RA is currently limited. Recently, we and others proved the importance of TNFα-induced protein (TNFAIP), due to the spontaneous development of arthritis in deficient animals that are dependent on IL-6. To date, nine TNFAIPs have been identified, and TNFAIP3 and TNFAIP9 were found to be clearly associated with mouse and human arthritis. In this review, we compare and discuss recent TNFAIP topics, especially focusing on TNFAIP3 and TNFAIP9 in autoimmune arthritis in mice and humans. © 2014 Published by Elsevier Inc.
C
KEYWORDS
14
E
13
T
11
15
R
R
19
O
31 32
37 38 39 40
N
36
Contents
1. TNFAIP3 and arthritis . . . . . . . . . . . . . . . . . . . . 2. TNFAIP9 in arthritis . . . . . . . . . . . . . . . . . . . . . 3. Relationship between TNFAIP3 and TNFAIP9 in arthritis . 4. Future directions . . . . . . . . . . . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . .
U
35
C
33 34
F
O
Q53
Regulatory roles of tumor necrosis factor alpha-induced proteins (TNFAIPs) 3 and 9 in arthritis
R O
2Q4
REVIEW
P
1
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
0 0 0 0 0 0
⁎ Corresponding author at: Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan. Fax: +81 29 853 3186. E-mail address: [email protected] (I. Matsumoto).
http://dx.doi.org/10.1016/j.clim.2014.03.015 1521-6616 © 2014 Published by Elsevier Inc. Please cite this article as: I. Matsumoto, et al., Regulatory roles of tumor necrosis factor alpha-induced proteins (TNFAIPs) 3 and 9 in arthritis, Clin. Immunol. (2014), http://dx.doi.org/10.1016/j.clim.2014.03.015
20 21 22 23 24 25 26 27 28 29 30
Q6
2 41 42 43
I. Matsumoto et al. Author contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
44
53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73
76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94
95
TNFAIP9 (also known as TIARP, STAMP2 and STEAP4 in humans) was first detected in the course of adipocyte differentiation [12], induced by both TNFα and IL-6 [13]. In murine hepatocytes, TNFα and IL-17 synergistically induce the upregulation of TNFAIP9 [14], and the TNFAIP9 gene was identified as a direct target of phosphorylated STAT3 [15]. Using GeneChip analysis, upregulation of TNFAIP9 was noted
96
N C O U Q2
75
2. TNFAIP9 in arthritis
R
74
F
52
O
51
R O
50
C
49
E
48
R
47
P
NF-κB signaling is a well described pathway which induces the transcription of numerous pro-inflammatory and survival genes. TNFAIP3 (also known as A20) is known to be a deubiquitinating protein that negatively regulates NF-κB dependent gene expression [1]. TNFα can induce TNFAIP3 mRNA in almost all tissues and many cells. TNFAIP3 regulates multiple ubiquitin dependent pathways, including those downstream of TNFreceptor1, IL-1 receptor/Toll like receptor 4, and NOD-like receptor, and cleaves polyubiquitin chains (Fig. 1) [2,3]. Mice with complete-deficiency of TNFAIP3 develop severe inflammation and cachexia, and die prematurely [4]. Matmati et al. recently made myeloid specific-TNFAIP3 deficient (TNFAIP3−/−) mice that develop spontaneous polyarthritis [5]. Arthritis appeared at 8– 12 weeks, and the incidence of arthritis reached 100% by 20 weeks. However, these mice did not show any signs of inflammation except at joints. High levels of inflammatory cytokines such as TNFα, IL-6, IL-1β and MCP-1 were noted in serum. These mice had elevated levels of anti-type II collagen autoantibodies, suggesting the development of autoimmunity. They had a higher percentage of T helper 17 (Th17) cells, memory CD4+ cells and CD8+ cells in lymph nodes and splenocytes, and an increase in CD11b+Gr-1+ cells in splenocytes was noted. Differentiation of osteoclasts by RANK ligand and macrophage colony stimulating factor was accelerated. Using thioglycollate induced peritoneal macrophages, sustained degradation of the NF-κB inhibitory molecule, IκBα, was seen. Lipopolysaccharide (LPS) induced higher levels of TNFα in macrophages of TNFAIP3−/− mice.
D
46
Interestingly, despite the upregulation of several inflammatory cytokines in serum, this arthritis is clearly dependent on IL-6, because significant protection was obtained by therapeutic treatment with IL-6 neutralizing antibodies, whereas it was independent of TNFα, T cells, and B cells. The problem with TNFAIP3 is that specific cell type deficient mice exhibit different autoimmune phenotypes [6], highlighting the pivotal role of macrophages in TNF-dependent pathway of arthritis. Table 1 shows the differences between TNFAIP3 and TNFAIP9 in arthritic conditions. In humans, this molecule is especially studied due to genome wide association with RA [7,8]. These associated single nucleotide polymorphisms (SNPs) are located outside the coding region, suggesting that they play a role in susceptibility by reducing TNFAIP3 expression. Moreover, the genetic relationship to TNFAIP3 was shown in many inflammatory and autoimmune diseases [9]. The expression of TNFAIP3 was reported to be upregulated in human PBMC compared to healthy subjects [10], and was different from that of osteoarthritis in joints [11].
E
1. TNFAIP3 and arthritis
T
45 Q7
Figure 1 NF-κB and STAT3 signaling pathways can be regulated by TNFAIP3 and TNFAIP9. TNFAIP3 regulates NF-κB pathway by deubiquitinating TNFR1-RIP1, IL-1R/TLR4-TRAF6, and NOD2-RIP2 pathways. On the other hand, TNFAIP9 regulates degradation of the NF-κB inhibitory molecule IκBα, and phospho-STAT3. Please cite this article as: I. Matsumoto, et al., Regulatory roles of tumor necrosis factor alpha-induced proteins (TNFAIPs) 3 and 9 in arthritis, Clin. Immunol. (2014), http://dx.doi.org/10.1016/j.clim.2014.03.015
97 98 99 100 101 102
TNFAIP3 and 9 in arthritis
3
t1:1Q3 t1:2 t1:3
Table 1 Molecules
TNFAIP3
TNFAIP9
t1:4 t1:5 t1:6 t1:7 t1:8 t1:9 t1:10 t1:11 t1:12 t1:13 t1:14 t1:15 t1:16 t1:17 t1:18 t1:19
Other names Dominant expressing cells (arthritic condition) Cytokines that can upregulate Arthritic animals Arthritis phenotype Other phenotype Induction by collagen induced arthritis Arthritis onset Upregulated serum cytokines Regulated signal transduction Increased cells in spleen Inhibition of arthritis by cytokines Human SNP association RA PBMC RA synovium
A20 All cells TNFα
TIARP, STAMP2, STEAP4 Macrophage, neutrophil, synoviocytes TNFα, IL-6, IL-1β
Myeloid-conditional deficient None Not known 8–20 weeks TNFα, IL-6, IL-1β NF-κB CD11b +, memory CD4 (Th17), CD8 IL-6
Whole deficient Mild infiltrate in white adipose tissue Exacerbated 24–48 weeks IL-6 only NF-κB, STAT3 CD11b +, Th1 and Th17 (in CIA) IL-6
Yes Elevated Yes
Not known Elevated (monocytes, neutrophils) Yes
111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143
F
O
R O
3. Relationship between TNFAIP3 and TNFAIP9 in arthritis
162
As discussed above, there is evidence that TNFAIP3 and TNFAIP9 are both crucial in arthritic conditions, especially in macrophages. We first checked the course of TNFAIP3 in GPIinduced arthritis and compared it to the expression of TNFAIP9. GPI-induced arthritis is clearly dependent both on TNFα and IL-6 [24,25], and arthritis suppression seems to be associated with TNFAIP9 [16]. As shown in Fig. 2, the time course expression of TNFAIP3 was initially high, downregulated on day 7 (arthritis onset), then gradually increased in the spleen. In joints, TNFAIP3 expression peaked on day 14, and seemed to be correlated with joint swelling. TNFAIP9 expression in the spleen and joints seemed to be the reverse of that of TNFAIP3. Until now, the link between TNFAIP3 and TNFAIP9 has not been defined; thus, we checked TNFAIP3 expression in WT and TNFAIP9−/− macrophages stimulated by TNFα, IL-6 and LPS. TNFAIP3 and TNFAIP9 mRNA were clearly upregulated after TNFα and LPS stimulation within 3 h of culture. The expression of TNFAIP3 was comparable in both
164
D
P
144
E
110
structure of STEAP4 was recently identified [21]. STEAP4 was found to be highly expressed in peripheral blood and CD68+ cells of the synovium of patients with RA [16,20]. In a cultured synovial fibroblast cell line, STEAP4 expression was augmented by TNFα activation, and the protein was found to be localized in endosomal/lysosomal compartments [22]. STEAP4 downregulation by RNA interference enhanced the expression of IL-6 mRNA, while STEAP4 overexpression suppressed IL-6 and IL-8 expressions, inhibited cell proliferation, and induced apoptosis [22]. In human peripheral blood of patients with RA, STEAP4 expression was detected in the plasma membranes of monocytes and neutrophils, and could be strongly downregulated by the TNFα antagonist, infliximab, especially in those patients with RA who showed a good clinical response [23]. These findings suggest that STEAP4 may function as a negative regulator in the inflammatory and proliferative state of arthritis, especially in TNFα-induced conditions.
T
109
C
108
E
107
R
106
R
105
in a TNFα-dependent arthritis models, such as glucose6-phosphate isomerase (GPI)-induced arthritis, and expressed mainly in macrophages, neutrophils and synoviocytes in arthritic conditions in mice [16]. We recently determined that TNFAIP9-deficient (TNFAIP9−/−) mice develop spontaneous arthritis. Around 80% of our deficient mice developed joint abnormalities by 12 months of age [17]. The white adipose tissue showed weak cell infiltration, confirming the report of Wellen et al. [18]; however, no other tissue abnormalities were seen in TNFAIP9−/−. High levels of serum IL-6 were seen in TNFAIP9−/− mice irrespective of age, whereas no TNFα or GM-CSF was detected, and IL-1β was similar to that in wild-type (WT) mice. Elevated numbers of CD11b+Gr1low + mid cells were seen in the spleen; however, the involvement of acquired immune cells in the thymus, spleen and lymph nodes (MLN) was similar to WT. Thioglycolate-activated peritoneal macrophages from TNFAIP9−/− mice produced greater amounts of IL-6, TNFα and IL-1β with LPS stimulation. In addition, TNFAIP9−/− macrophages produced greater amounts of IL-6 with TNFα stimulation. TNFAIP9−/− macrophages enhanced NF-κB signaling and dysregulated TNFα-induced apoptosis and increased IL-6-induced STAT3 phosphorylation. After TNFα-stimulation, sustained degradation of IκBα was noted, and subsequent proliferation with dysregulated apoptosis was seen in TNFAIP9−/− macrophages. Moreover, IL-6 induced phosphorylated STAT3 also increased in TNFAIP9−/− macrophages, whereas pErk1/2 production did not change. These comparisons are summarized in Fig. 1. Collagen-induced arthritis (CIA) development was markedly exacerbated in TNFAIP9−/− mice, and their CD4 and CD8 cell counts were higher than in WT. Antigen-specific cytokine production such as IFNγ and IL-17 was higher in TNFAIP9−/− compared to WT mice in the draining LNs, and unexpectedly, antigen-specific anti-CII antibodies were comparable in TNFAIP9−/− and WT mice. Neutralization of IL-6 in the arthritis induction phase clearly suppressed arthritis, suggesting a pivotal role for IL-6. In humans, STEAP4 (TNFAIP9) is ubiquitously and highly expressed in non-neuronal tissues with relatively high levels in the pericardium, synovial membranes, placenta, adipose tissue, lung, heart, liver, and prostate [19,20]. The crystal
N C O
104
U
103
Comparison of characteristics of TNFAIP3 and TNFAIP9 in arthritis.
Please cite this article as: I. Matsumoto, et al., Regulatory roles of tumor necrosis factor alpha-induced proteins (TNFAIPs) 3 and 9 in arthritis, Clin. Immunol. (2014), http://dx.doi.org/10.1016/j.clim.2014.03.015
145 146 147 148 149 150 151 152 Q8 153 154 155 156 157 158 159 160 161
163
165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 Q9 180 181
I. Matsumoto et al.
P
R O
O
F
4
187 Q10
C
E
186
R
185
4. Future directions
188
As summarized, both TNFAIP3 and TNFAIP9 have pivotal roles in arthritis in mice, with some differences (Table 1). TNFAIP3 is expressed in almost all cells in mice; cell-specific conditional-deficient mice have revealed the function of
189 Q11
R
184
WT and TNFAIP9−/− when cultured with TNFα and LPS. In contrast, IL-6 stimulation could induce only TNFAIP9 in WT macrophages. When we compared it with TNFAIP9−/− macrophages, clear upregulation was observed in TNFAIP3 expression, suggesting an association between TNFAIP3 and TNFAIP9 in IL-6 cultured conditions. (See Fig. 3.)
N C O
183
U
182
T
E
D
Figure 2 Comparative expression of TNFAIP3 and TNFAIP9 in glucose-6-phosphate isomerase (GPI) induced arthritis. After GPI-immunization on day 0, at indicated time points, spleens and joints were isolated from GPI-induced arthritis, and analyzed by real-time-PCR. Real-time PCR was carried out using ABI7500 (Applied Biosystems) by using TNFAIP3 (Mm00437121_m1), TNFAIP9 (Mm00475402_m1) and GAPDH (Mm99999915_g1) primers. Analysis of post-PCR melting curves confirmed the specificity of the single target amplification. We determined the expression of each gene relative to Gapdh.
Figure 3 Comparative expression of TNFAIP3 and TNFAIP9 in thioglycolate-elicited macrophages (TEM), cultured in the presence of TNFα, IL-6 and LPS. TEM were elicited from TNFAIP9−/− mice or WT mice, 5 × 105 cells were cultured with TNFα (100 ng/ml), IL-6 (10 ng/ml) or LPS (100 ng/ml) for 3, 6, 12 and 24 h. Then the expression of TNFAIP3 and TNFAIP9 was analyzed and compared by real-time-PCR. *P b 0.05 by Student's t test. Please cite this article as: I. Matsumoto, et al., Regulatory roles of tumor necrosis factor alpha-induced proteins (TNFAIPs) 3 and 9 in arthritis, Clin. Immunol. (2014), http://dx.doi.org/10.1016/j.clim.2014.03.015
190 191 192
TNFAIP3 and 9 in arthritis
222
It has been proved that TNFα and IL-6 have a central role in the disease pathogenesis of RA. In this review we summarized and compared the roles of TNFAIP3 and TNFAIP9 and their relationship with pro-inflammatory cytokines in arthritis according to recent research. Additional research is required on the regulatory mechanisms of TNFAIP3 and TNFAIP9 in RA, and might open new therapeutic avenues along the “cytokine driven” pathways in RA.
223
Competing interests
224
The authors declare no competing interests.
225
Author contributions
226 Q14
229
All authors provided substantial contributions to the discussion of the contents and to the reviewing and editing of the manuscripts before submission. I Matsumoto and A Inoue researched the data and wrote the manuscripts.
230
Acknowledgments
231
235
This work was supported in part by a grant from The Japanese Ministry of Science and Culture (IM, TS, AI). We thank Brian K. Purdue, associate professor of English for Medical Purposes, Medical English Communications Center, University of Tsukuba, for his editorial assistance.
236
References
206 207 208 Q13 209 210 211 212
216 217 218 219 220 221
227 228
232 Q15 233 234
237 238 239 240 241
D
205 Q12
T
204
C
203
E
202
R
201
R
200
N C O
199
U
198
F
215
197
O
5. Conclusion
196
R O
214
195
[2] A. Ma, B.A. Malynn, A20: linking a complex regulator of ubiquitylation to immunity and human disease, Nat. Rev. Immunol. 12 (2012) 774–785. [3] K. Heyninck, D. De Valck, W. Vanden Berghe, W. Van Criekinge, R. Contreras, W. Fiers, et al., The zinc finger protein A20 inhibits TNF-induced NF-kappaB-dependent gene expression by interfering with an RIP- or TRAF2-mediated transactivation signal and directly binds to a novel NF-kappaB-inhibiting protein ABIN, J. Cell Biol. 145 (1999) 1471–1482. [4] E.G. Lee, D.L. Boone, S. Chai, S.L. Libby, M. Chien, J.P. Lodolce, et al., Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice, Science 289 (2000) 2350–2354. [5] M. Matmati, P. Jacques, J. Maelfait, E. Verheugen, M. Kool, M. Sze, et al., A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis, Nat. Genet. 43 (2011) 908–912. [6] F. Martin, V.M. Dixit, A20 edits ubiquitin and autoimmune paradigms, Nat. Genet. 43 (2011) 822–823. [7] R.M. Plenge, C. Cotsapas, L. Davies, A.L. Price, P.I. de Bakker, J. Maller, et al., Two independent alleles at 6q23 associated with risk of rheumatoid arthritis, Nat. Genet. 39 (2007) 1477–1482. [8] W. Thomson, A. Barton, X. Ke, S. Eyre, A. Hinks, J. Bowes, et al., Rheumatoid arthritis association at 6q23, Nat. Genet. 39 (2007) 1431–1433. [9] L. Vereecke, R. Beyaert, G. van Loo, Genetic relationships between A20/TNFAIP3, chronic inflammation and autoimmune disease, Biochem. Soc. Trans. 39 (2011) 1086–1091. [10] J.R. Maxwell, I.R. Gowers, K.P. Kuet, A. Barton, J. Worthington, A.G. Wilson, Expression of the autoimmunity associated TNFAIP3 is increased in rheumatoid arthritis but does not differ according to genotype at 6q23, Rheumatology (Oxford) 51 (2012) 1514–1515. [11] L.M. Elsby, G. Orozco, J. Denton, J. Worthington, D.W. Ray, R. P. Donn, Functional evaluation of TNFAIP3 (A20) in rheumatoid arthritis, Clin. Exp. Rheumatol. 28 (2010) 708–714. [12] M. Moldes, F. Lasnier, X. Gauthereau, C. Klein, J. Pairault, B. Feve, et al., Tumor necrosis factor-alpha-induced adiposerelated protein (TIARP), a cell-surface protein that is highly induced by tumor necrosis factor-alpha and adipose conversion, J. Biol. Chem. 276 (2001) 33938–33946. [13] M. Fasshauer, M. Kralisch, M. Klier, U. Lossner, M. Bluher, A.M. Chambaut-Guerin, et al., Interleukin-6 is a positive regulator of tumor necrosis factor alpha-induced adipose-related protein in 3T3-L1 adipocytes, FEBS Lett. 560 (2004) 153–157. [14] T. Sparna, J. Retey, K. Schmich, U. Albrecht, K. Naumann, N. Gretz, et al., Genome-wide comparison between IL-17 and combined TNF-alpha/IL-17 induced genes in primary murine hepatocytes, BMC Genomics 11 (2010) 226. [15] P. Ramadoss, F. Chiappini, M. Biban, A.N. Hollenberg, Regulation of hepatic six transmembrane epithelial antigen of prostate 4 (STEAP4) expression by STAT3 and CCAAT/enhancerbinding protein alpha, J. Biol. Chem. 285 (2010) 16453–16466. [16] A. Inoue, I. Matsumoto, Y. Tanaka, K. Iwanami, A. Kanamori, N. Ochiai, et al., Tumor necrosis factor alpha-induced adiposerelated protein expression in experimental arthritis and in rheumatoid arthritis, Arthritis Res. Ther. 11 (2009) R118. [17] A. Inoue, I. Matsumoto, Y. Tanaka, N. Umeda, Y. Tanaka, M. Mihara, et al., Murine tumor necrosis factor α-induced adiposerelated protein (tumor necrosis factor α-induced protein 9) deficiency leads to arthritis via interleukin-6 overproduction with enhanced NF-κB, STAT-3 signaling, and dysregulated apoptosis of macrophages, Arthritis Rheum. 64 (2012) 3877– 3885. [18] K.E. Wellen, R. Fucho, M.F. Gregor, M. Furuhashi, C. Morgan, T. Lindstad, et al., Coordinated regulation of nutrient and inflammatory response by STAMP2 is essential for metabolic homeostasis, Cell 129 (2007) 537–548.
P
213
cell-specific regulation. However, TNFAIP3 deficiency in specific cell types in mice results in different phenotypes in autoimmune diseases [6]. Several SNPs of TNFAIP3 have been identified. Thus further study is needed to examine the function of the specific SNPs and of the cells, which will probably lead to understanding of the mechanisms of several autoimmune diseases. As for TNFAIP9, macrophages, neutrophils and synoviocytes are the major expressing cells, suggesting a strong link to the innate immunity of arthritis. SNPs associated with TNFAIP9 should also be examined in future, because some SNPs have already been identified in patients with metabolic syndrome [26,27]. Arthritis in both TNFAIP3 and TNFAIP9 deficient mice is clearly dependent on IL-6. Thus it helped us to understand IL-6 dependency in human arthritis. As future target of investigation, agonists that can induce TNFAIP3 and TNFAIP9 are promising especially in macrophages. If agonists of TNFAIP9 are identified (in addition to TNFα and IL-6), we might be able to regulate most of the inflammation of arthritis, because TNFAIP9 expression is seen in specific inflammatory cells in the arthritic condition.
194
E
193
5
[1] I.E. Wertz, K.M. O'Rourke, H. Zhou, M. Eby, L. Aravind, S. Seshagiri, P. Wu, C. Wiesmann, R. Baker, D.L. Boone, A. Ma, E. V. Koonin, V.M. Dixit, De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling, Nature 430 (2004) 694–699.
Please cite this article as: I. Matsumoto, et al., Regulatory roles of tumor necrosis factor alpha-induced proteins (TNFAIPs) 3 and 9 in arthritis, Clin. Immunol. (2014), http://dx.doi.org/10.1016/j.clim.2014.03.015
242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 Q16 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309
6 [19] T.G. Grunewald, H. Bach, A. Cossarizza, I. Matsumoto, The STEAP protein family: versatile oxidoreductases and targets for cancer immunotherapy with overlapping and distinct cellular functions, Biol. Cell. 104 (2012) 641–657. [20] C.G. Korkmanz, K.S. Korkmanz, P. Kurys, C. Elbi, L. Wang, T.I. Klokk, et al., Molecular cloning and characterization of STAMP2, an androgen-regulated six transmembrane protein that is overexpressed in prostate cancer, Oncogene 24 (2005) 4934–4945. [21] G.H. Gauss, M.D. Kleven, A.K. Sendamarai, M.D. Fleming, C.M. Lawrence, The crystal structure of six-transmembrane epithelial antigen of the prostate 4 (STEAP4), a ferri/cuprireductase, suggests a novel interdomain flavin-binding site, J. Biol. Chem. 288 (2013) 20668–20682. [22] Y. Tanaka, I. Matsumoto, K. Iwanami, A. Inoue, R. Minami, N. Umeda, et al., Six-transmembrane epithelial antigen of prostate4 (STEAP4) is a tumor necrosis factor alpha-induced protein that regulates IL-6, IL-8, and cell proliferation in synovium from patients with rheumatoid arthritis, Mod. Rheumatol. 22 (2012) 128–136. [23] Y. Tanaka, I. Matsumoto, K. Iwanami, A. Inoue, N. Umeda, Y. Tanaka, et al., Six-transmembrane epithelial antigen of
[24]
[25]
N C O
R
R
E
C
T
E
D
P
R O
[27]
O
F
[26]
prostate4 (STEAP4) is expressed on monocytes/neutrophils, and is regulated by TNF antagonist in patients with rheumatoid arthritis, Clin. Exp. Rheumatol. 30 (2012) 99–102. I. Matsumoto, H. Zhang, T. Yasukochi, K. Iwanami, Y. Tanaka, A. Inoue, et al., Therapeutic effects of antibodies to tumor necrosis factor-alpha, interleukin-6 and cytotoxic T-lymphocyte antigen 4 immunoglobulin in mice with glucose-6-phosphate isomerase induced arthritis, Arthritis Res. Ther. 10 (2008) R66. K. Iwanami, I. Matsumoto, Y. Tanaka-Watanabe, A. Inoue, M. Mihara, Y. Ohsugi, et al., Crucial role of the interleukin-6/ interleukin-17 cytokine axis in the induction of arthritis by glucose-6-phosphate isomerase, Arthritis Rheum. 58 (2008) 754–763. T. Wangensteen, H. Akselsen, J. Holmen, D. Undlien, L. Retterstøl, A common haplotype in NAPEPLD is associated with severe obesity in a Norwegian population-based cohort (the HUNT study), Obesity (Silver Spring) 19 (2011) 612–617. Y.Y. Guo, N.F. Li, L. Zhou, X.G. Yao, H.M. Wang, J.H. Zhang, et al., A common variation within the STEAP4 gene exons is associated with obesity in Uygur general population, Chin. Med. J. (Engl.) 124 (2011) 2096–2100.
U
310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 354
I. Matsumoto et al.
Please cite this article as: I. Matsumoto, et al., Regulatory roles of tumor necrosis factor alpha-induced proteins (TNFAIPs) 3 and 9 in arthritis, Clin. Immunol. (2014), http://dx.doi.org/10.1016/j.clim.2014.03.015
332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353
available at www.sciencedirect.com
Clinical Immunology www.elsevier.com/locate/yclim
4
5Q1 6
7 8
Isao Matsumoto ⁎, Asuka Inoue, Chinatsu Takai, Naoto Umeda, Yuki Tanaka, Yuko Kurashima, Takayuki Sumida Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
D
9
Received 5 February 2014; 24 March 2014; accepted with revision 25 March 2014
E
10
Rheumatoid arthritis; TNFα; IL-6; TNFAIP3; TNFAIP9
16 17 18
Abstract Tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) have proved to be important in rheumatoid arthritis (RA) because the outcome of RA has greatly improved with the recent availability of biologics targeting them. It is well accepted that these cytokines are involved in the activation of the nuclear factor-κB (NF-κB) signaling pathway, but our understanding of the dependency of these pro-inflammatory cytokines and the link between them in RA is currently limited. Recently, we and others proved the importance of TNFα-induced protein (TNFAIP), due to the spontaneous development of arthritis in deficient animals that are dependent on IL-6. To date, nine TNFAIPs have been identified, and TNFAIP3 and TNFAIP9 were found to be clearly associated with mouse and human arthritis. In this review, we compare and discuss recent TNFAIP topics, especially focusing on TNFAIP3 and TNFAIP9 in autoimmune arthritis in mice and humans. © 2014 Published by Elsevier Inc.
C
KEYWORDS
14
E
13
T
11
15
R
R
19
O
31 32
37 38 39 40
N
36
Contents
1. TNFAIP3 and arthritis . . . . . . . . . . . . . . . . . . . . 2. TNFAIP9 in arthritis . . . . . . . . . . . . . . . . . . . . . 3. Relationship between TNFAIP3 and TNFAIP9 in arthritis . 4. Future directions . . . . . . . . . . . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . .
U
35
C
33 34
F
O
Q53
Regulatory roles of tumor necrosis factor alpha-induced proteins (TNFAIPs) 3 and 9 in arthritis
R O
2Q4
REVIEW
P
1
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
0 0 0 0 0 0
⁎ Corresponding author at: Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan. Fax: +81 29 853 3186. E-mail address: [email protected] (I. Matsumoto).
http://dx.doi.org/10.1016/j.clim.2014.03.015 1521-6616 © 2014 Published by Elsevier Inc. Please cite this article as: I. Matsumoto, et al., Regulatory roles of tumor necrosis factor alpha-induced proteins (TNFAIPs) 3 and 9 in arthritis, Clin. Immunol. (2014), http://dx.doi.org/10.1016/j.clim.2014.03.015
20 21 22 23 24 25 26 27 28 29 30
Q6
2 41 42 43
I. Matsumoto et al. Author contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
44
53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73
76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94
95
TNFAIP9 (also known as TIARP, STAMP2 and STEAP4 in humans) was first detected in the course of adipocyte differentiation [12], induced by both TNFα and IL-6 [13]. In murine hepatocytes, TNFα and IL-17 synergistically induce the upregulation of TNFAIP9 [14], and the TNFAIP9 gene was identified as a direct target of phosphorylated STAT3 [15]. Using GeneChip analysis, upregulation of TNFAIP9 was noted
96
N C O U Q2
75
2. TNFAIP9 in arthritis
R
74
F
52
O
51
R O
50
C
49
E
48
R
47
P
NF-κB signaling is a well described pathway which induces the transcription of numerous pro-inflammatory and survival genes. TNFAIP3 (also known as A20) is known to be a deubiquitinating protein that negatively regulates NF-κB dependent gene expression [1]. TNFα can induce TNFAIP3 mRNA in almost all tissues and many cells. TNFAIP3 regulates multiple ubiquitin dependent pathways, including those downstream of TNFreceptor1, IL-1 receptor/Toll like receptor 4, and NOD-like receptor, and cleaves polyubiquitin chains (Fig. 1) [2,3]. Mice with complete-deficiency of TNFAIP3 develop severe inflammation and cachexia, and die prematurely [4]. Matmati et al. recently made myeloid specific-TNFAIP3 deficient (TNFAIP3−/−) mice that develop spontaneous polyarthritis [5]. Arthritis appeared at 8– 12 weeks, and the incidence of arthritis reached 100% by 20 weeks. However, these mice did not show any signs of inflammation except at joints. High levels of inflammatory cytokines such as TNFα, IL-6, IL-1β and MCP-1 were noted in serum. These mice had elevated levels of anti-type II collagen autoantibodies, suggesting the development of autoimmunity. They had a higher percentage of T helper 17 (Th17) cells, memory CD4+ cells and CD8+ cells in lymph nodes and splenocytes, and an increase in CD11b+Gr-1+ cells in splenocytes was noted. Differentiation of osteoclasts by RANK ligand and macrophage colony stimulating factor was accelerated. Using thioglycollate induced peritoneal macrophages, sustained degradation of the NF-κB inhibitory molecule, IκBα, was seen. Lipopolysaccharide (LPS) induced higher levels of TNFα in macrophages of TNFAIP3−/− mice.
D
46
Interestingly, despite the upregulation of several inflammatory cytokines in serum, this arthritis is clearly dependent on IL-6, because significant protection was obtained by therapeutic treatment with IL-6 neutralizing antibodies, whereas it was independent of TNFα, T cells, and B cells. The problem with TNFAIP3 is that specific cell type deficient mice exhibit different autoimmune phenotypes [6], highlighting the pivotal role of macrophages in TNF-dependent pathway of arthritis. Table 1 shows the differences between TNFAIP3 and TNFAIP9 in arthritic conditions. In humans, this molecule is especially studied due to genome wide association with RA [7,8]. These associated single nucleotide polymorphisms (SNPs) are located outside the coding region, suggesting that they play a role in susceptibility by reducing TNFAIP3 expression. Moreover, the genetic relationship to TNFAIP3 was shown in many inflammatory and autoimmune diseases [9]. The expression of TNFAIP3 was reported to be upregulated in human PBMC compared to healthy subjects [10], and was different from that of osteoarthritis in joints [11].
E
1. TNFAIP3 and arthritis
T
45 Q7
Figure 1 NF-κB and STAT3 signaling pathways can be regulated by TNFAIP3 and TNFAIP9. TNFAIP3 regulates NF-κB pathway by deubiquitinating TNFR1-RIP1, IL-1R/TLR4-TRAF6, and NOD2-RIP2 pathways. On the other hand, TNFAIP9 regulates degradation of the NF-κB inhibitory molecule IκBα, and phospho-STAT3. Please cite this article as: I. Matsumoto, et al., Regulatory roles of tumor necrosis factor alpha-induced proteins (TNFAIPs) 3 and 9 in arthritis, Clin. Immunol. (2014), http://dx.doi.org/10.1016/j.clim.2014.03.015
97 98 99 100 101 102
TNFAIP3 and 9 in arthritis
3
t1:1Q3 t1:2 t1:3
Table 1 Molecules
TNFAIP3
TNFAIP9
t1:4 t1:5 t1:6 t1:7 t1:8 t1:9 t1:10 t1:11 t1:12 t1:13 t1:14 t1:15 t1:16 t1:17 t1:18 t1:19
Other names Dominant expressing cells (arthritic condition) Cytokines that can upregulate Arthritic animals Arthritis phenotype Other phenotype Induction by collagen induced arthritis Arthritis onset Upregulated serum cytokines Regulated signal transduction Increased cells in spleen Inhibition of arthritis by cytokines Human SNP association RA PBMC RA synovium
A20 All cells TNFα
TIARP, STAMP2, STEAP4 Macrophage, neutrophil, synoviocytes TNFα, IL-6, IL-1β
Myeloid-conditional deficient None Not known 8–20 weeks TNFα, IL-6, IL-1β NF-κB CD11b +, memory CD4 (Th17), CD8 IL-6
Whole deficient Mild infiltrate in white adipose tissue Exacerbated 24–48 weeks IL-6 only NF-κB, STAT3 CD11b +, Th1 and Th17 (in CIA) IL-6
Yes Elevated Yes
Not known Elevated (monocytes, neutrophils) Yes
111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143
F
O
R O
3. Relationship between TNFAIP3 and TNFAIP9 in arthritis
162
As discussed above, there is evidence that TNFAIP3 and TNFAIP9 are both crucial in arthritic conditions, especially in macrophages. We first checked the course of TNFAIP3 in GPIinduced arthritis and compared it to the expression of TNFAIP9. GPI-induced arthritis is clearly dependent both on TNFα and IL-6 [24,25], and arthritis suppression seems to be associated with TNFAIP9 [16]. As shown in Fig. 2, the time course expression of TNFAIP3 was initially high, downregulated on day 7 (arthritis onset), then gradually increased in the spleen. In joints, TNFAIP3 expression peaked on day 14, and seemed to be correlated with joint swelling. TNFAIP9 expression in the spleen and joints seemed to be the reverse of that of TNFAIP3. Until now, the link between TNFAIP3 and TNFAIP9 has not been defined; thus, we checked TNFAIP3 expression in WT and TNFAIP9−/− macrophages stimulated by TNFα, IL-6 and LPS. TNFAIP3 and TNFAIP9 mRNA were clearly upregulated after TNFα and LPS stimulation within 3 h of culture. The expression of TNFAIP3 was comparable in both
164
D
P
144
E
110
structure of STEAP4 was recently identified [21]. STEAP4 was found to be highly expressed in peripheral blood and CD68+ cells of the synovium of patients with RA [16,20]. In a cultured synovial fibroblast cell line, STEAP4 expression was augmented by TNFα activation, and the protein was found to be localized in endosomal/lysosomal compartments [22]. STEAP4 downregulation by RNA interference enhanced the expression of IL-6 mRNA, while STEAP4 overexpression suppressed IL-6 and IL-8 expressions, inhibited cell proliferation, and induced apoptosis [22]. In human peripheral blood of patients with RA, STEAP4 expression was detected in the plasma membranes of monocytes and neutrophils, and could be strongly downregulated by the TNFα antagonist, infliximab, especially in those patients with RA who showed a good clinical response [23]. These findings suggest that STEAP4 may function as a negative regulator in the inflammatory and proliferative state of arthritis, especially in TNFα-induced conditions.
T
109
C
108
E
107
R
106
R
105
in a TNFα-dependent arthritis models, such as glucose6-phosphate isomerase (GPI)-induced arthritis, and expressed mainly in macrophages, neutrophils and synoviocytes in arthritic conditions in mice [16]. We recently determined that TNFAIP9-deficient (TNFAIP9−/−) mice develop spontaneous arthritis. Around 80% of our deficient mice developed joint abnormalities by 12 months of age [17]. The white adipose tissue showed weak cell infiltration, confirming the report of Wellen et al. [18]; however, no other tissue abnormalities were seen in TNFAIP9−/−. High levels of serum IL-6 were seen in TNFAIP9−/− mice irrespective of age, whereas no TNFα or GM-CSF was detected, and IL-1β was similar to that in wild-type (WT) mice. Elevated numbers of CD11b+Gr1low + mid cells were seen in the spleen; however, the involvement of acquired immune cells in the thymus, spleen and lymph nodes (MLN) was similar to WT. Thioglycolate-activated peritoneal macrophages from TNFAIP9−/− mice produced greater amounts of IL-6, TNFα and IL-1β with LPS stimulation. In addition, TNFAIP9−/− macrophages produced greater amounts of IL-6 with TNFα stimulation. TNFAIP9−/− macrophages enhanced NF-κB signaling and dysregulated TNFα-induced apoptosis and increased IL-6-induced STAT3 phosphorylation. After TNFα-stimulation, sustained degradation of IκBα was noted, and subsequent proliferation with dysregulated apoptosis was seen in TNFAIP9−/− macrophages. Moreover, IL-6 induced phosphorylated STAT3 also increased in TNFAIP9−/− macrophages, whereas pErk1/2 production did not change. These comparisons are summarized in Fig. 1. Collagen-induced arthritis (CIA) development was markedly exacerbated in TNFAIP9−/− mice, and their CD4 and CD8 cell counts were higher than in WT. Antigen-specific cytokine production such as IFNγ and IL-17 was higher in TNFAIP9−/− compared to WT mice in the draining LNs, and unexpectedly, antigen-specific anti-CII antibodies were comparable in TNFAIP9−/− and WT mice. Neutralization of IL-6 in the arthritis induction phase clearly suppressed arthritis, suggesting a pivotal role for IL-6. In humans, STEAP4 (TNFAIP9) is ubiquitously and highly expressed in non-neuronal tissues with relatively high levels in the pericardium, synovial membranes, placenta, adipose tissue, lung, heart, liver, and prostate [19,20]. The crystal
N C O
104
U
103
Comparison of characteristics of TNFAIP3 and TNFAIP9 in arthritis.
Please cite this article as: I. Matsumoto, et al., Regulatory roles of tumor necrosis factor alpha-induced proteins (TNFAIPs) 3 and 9 in arthritis, Clin. Immunol. (2014), http://dx.doi.org/10.1016/j.clim.2014.03.015
145 146 147 148 149 150 151 152 Q8 153 154 155 156 157 158 159 160 161
163
165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 Q9 180 181
I. Matsumoto et al.
P
R O
O
F
4
187 Q10
C
E
186
R
185
4. Future directions
188
As summarized, both TNFAIP3 and TNFAIP9 have pivotal roles in arthritis in mice, with some differences (Table 1). TNFAIP3 is expressed in almost all cells in mice; cell-specific conditional-deficient mice have revealed the function of
189 Q11
R
184
WT and TNFAIP9−/− when cultured with TNFα and LPS. In contrast, IL-6 stimulation could induce only TNFAIP9 in WT macrophages. When we compared it with TNFAIP9−/− macrophages, clear upregulation was observed in TNFAIP3 expression, suggesting an association between TNFAIP3 and TNFAIP9 in IL-6 cultured conditions. (See Fig. 3.)
N C O
183
U
182
T
E
D
Figure 2 Comparative expression of TNFAIP3 and TNFAIP9 in glucose-6-phosphate isomerase (GPI) induced arthritis. After GPI-immunization on day 0, at indicated time points, spleens and joints were isolated from GPI-induced arthritis, and analyzed by real-time-PCR. Real-time PCR was carried out using ABI7500 (Applied Biosystems) by using TNFAIP3 (Mm00437121_m1), TNFAIP9 (Mm00475402_m1) and GAPDH (Mm99999915_g1) primers. Analysis of post-PCR melting curves confirmed the specificity of the single target amplification. We determined the expression of each gene relative to Gapdh.
Figure 3 Comparative expression of TNFAIP3 and TNFAIP9 in thioglycolate-elicited macrophages (TEM), cultured in the presence of TNFα, IL-6 and LPS. TEM were elicited from TNFAIP9−/− mice or WT mice, 5 × 105 cells were cultured with TNFα (100 ng/ml), IL-6 (10 ng/ml) or LPS (100 ng/ml) for 3, 6, 12 and 24 h. Then the expression of TNFAIP3 and TNFAIP9 was analyzed and compared by real-time-PCR. *P b 0.05 by Student's t test. Please cite this article as: I. Matsumoto, et al., Regulatory roles of tumor necrosis factor alpha-induced proteins (TNFAIPs) 3 and 9 in arthritis, Clin. Immunol. (2014), http://dx.doi.org/10.1016/j.clim.2014.03.015
190 191 192
TNFAIP3 and 9 in arthritis
222
It has been proved that TNFα and IL-6 have a central role in the disease pathogenesis of RA. In this review we summarized and compared the roles of TNFAIP3 and TNFAIP9 and their relationship with pro-inflammatory cytokines in arthritis according to recent research. Additional research is required on the regulatory mechanisms of TNFAIP3 and TNFAIP9 in RA, and might open new therapeutic avenues along the “cytokine driven” pathways in RA.
223
Competing interests
224
The authors declare no competing interests.
225
Author contributions
226 Q14
229
All authors provided substantial contributions to the discussion of the contents and to the reviewing and editing of the manuscripts before submission. I Matsumoto and A Inoue researched the data and wrote the manuscripts.
230
Acknowledgments
231
235
This work was supported in part by a grant from The Japanese Ministry of Science and Culture (IM, TS, AI). We thank Brian K. Purdue, associate professor of English for Medical Purposes, Medical English Communications Center, University of Tsukuba, for his editorial assistance.
236
References
206 207 208 Q13 209 210 211 212
216 217 218 219 220 221
227 228
232 Q15 233 234
237 238 239 240 241
D
205 Q12
T
204
C
203
E
202
R
201
R
200
N C O
199
U
198
F
215
197
O
5. Conclusion
196
R O
214
195
[2] A. Ma, B.A. Malynn, A20: linking a complex regulator of ubiquitylation to immunity and human disease, Nat. Rev. Immunol. 12 (2012) 774–785. [3] K. Heyninck, D. De Valck, W. Vanden Berghe, W. Van Criekinge, R. Contreras, W. Fiers, et al., The zinc finger protein A20 inhibits TNF-induced NF-kappaB-dependent gene expression by interfering with an RIP- or TRAF2-mediated transactivation signal and directly binds to a novel NF-kappaB-inhibiting protein ABIN, J. Cell Biol. 145 (1999) 1471–1482. [4] E.G. Lee, D.L. Boone, S. Chai, S.L. Libby, M. Chien, J.P. Lodolce, et al., Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice, Science 289 (2000) 2350–2354. [5] M. Matmati, P. Jacques, J. Maelfait, E. Verheugen, M. Kool, M. Sze, et al., A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis, Nat. Genet. 43 (2011) 908–912. [6] F. Martin, V.M. Dixit, A20 edits ubiquitin and autoimmune paradigms, Nat. Genet. 43 (2011) 822–823. [7] R.M. Plenge, C. Cotsapas, L. Davies, A.L. Price, P.I. de Bakker, J. Maller, et al., Two independent alleles at 6q23 associated with risk of rheumatoid arthritis, Nat. Genet. 39 (2007) 1477–1482. [8] W. Thomson, A. Barton, X. Ke, S. Eyre, A. Hinks, J. Bowes, et al., Rheumatoid arthritis association at 6q23, Nat. Genet. 39 (2007) 1431–1433. [9] L. Vereecke, R. Beyaert, G. van Loo, Genetic relationships between A20/TNFAIP3, chronic inflammation and autoimmune disease, Biochem. Soc. Trans. 39 (2011) 1086–1091. [10] J.R. Maxwell, I.R. Gowers, K.P. Kuet, A. Barton, J. Worthington, A.G. Wilson, Expression of the autoimmunity associated TNFAIP3 is increased in rheumatoid arthritis but does not differ according to genotype at 6q23, Rheumatology (Oxford) 51 (2012) 1514–1515. [11] L.M. Elsby, G. Orozco, J. Denton, J. Worthington, D.W. Ray, R. P. Donn, Functional evaluation of TNFAIP3 (A20) in rheumatoid arthritis, Clin. Exp. Rheumatol. 28 (2010) 708–714. [12] M. Moldes, F. Lasnier, X. Gauthereau, C. Klein, J. Pairault, B. Feve, et al., Tumor necrosis factor-alpha-induced adiposerelated protein (TIARP), a cell-surface protein that is highly induced by tumor necrosis factor-alpha and adipose conversion, J. Biol. Chem. 276 (2001) 33938–33946. [13] M. Fasshauer, M. Kralisch, M. Klier, U. Lossner, M. Bluher, A.M. Chambaut-Guerin, et al., Interleukin-6 is a positive regulator of tumor necrosis factor alpha-induced adipose-related protein in 3T3-L1 adipocytes, FEBS Lett. 560 (2004) 153–157. [14] T. Sparna, J. Retey, K. Schmich, U. Albrecht, K. Naumann, N. Gretz, et al., Genome-wide comparison between IL-17 and combined TNF-alpha/IL-17 induced genes in primary murine hepatocytes, BMC Genomics 11 (2010) 226. [15] P. Ramadoss, F. Chiappini, M. Biban, A.N. Hollenberg, Regulation of hepatic six transmembrane epithelial antigen of prostate 4 (STEAP4) expression by STAT3 and CCAAT/enhancerbinding protein alpha, J. Biol. Chem. 285 (2010) 16453–16466. [16] A. Inoue, I. Matsumoto, Y. Tanaka, K. Iwanami, A. Kanamori, N. Ochiai, et al., Tumor necrosis factor alpha-induced adiposerelated protein expression in experimental arthritis and in rheumatoid arthritis, Arthritis Res. Ther. 11 (2009) R118. [17] A. Inoue, I. Matsumoto, Y. Tanaka, N. Umeda, Y. Tanaka, M. Mihara, et al., Murine tumor necrosis factor α-induced adiposerelated protein (tumor necrosis factor α-induced protein 9) deficiency leads to arthritis via interleukin-6 overproduction with enhanced NF-κB, STAT-3 signaling, and dysregulated apoptosis of macrophages, Arthritis Rheum. 64 (2012) 3877– 3885. [18] K.E. Wellen, R. Fucho, M.F. Gregor, M. Furuhashi, C. Morgan, T. Lindstad, et al., Coordinated regulation of nutrient and inflammatory response by STAMP2 is essential for metabolic homeostasis, Cell 129 (2007) 537–548.
P
213
cell-specific regulation. However, TNFAIP3 deficiency in specific cell types in mice results in different phenotypes in autoimmune diseases [6]. Several SNPs of TNFAIP3 have been identified. Thus further study is needed to examine the function of the specific SNPs and of the cells, which will probably lead to understanding of the mechanisms of several autoimmune diseases. As for TNFAIP9, macrophages, neutrophils and synoviocytes are the major expressing cells, suggesting a strong link to the innate immunity of arthritis. SNPs associated with TNFAIP9 should also be examined in future, because some SNPs have already been identified in patients with metabolic syndrome [26,27]. Arthritis in both TNFAIP3 and TNFAIP9 deficient mice is clearly dependent on IL-6. Thus it helped us to understand IL-6 dependency in human arthritis. As future target of investigation, agonists that can induce TNFAIP3 and TNFAIP9 are promising especially in macrophages. If agonists of TNFAIP9 are identified (in addition to TNFα and IL-6), we might be able to regulate most of the inflammation of arthritis, because TNFAIP9 expression is seen in specific inflammatory cells in the arthritic condition.
194
E
193
5
[1] I.E. Wertz, K.M. O'Rourke, H. Zhou, M. Eby, L. Aravind, S. Seshagiri, P. Wu, C. Wiesmann, R. Baker, D.L. Boone, A. Ma, E. V. Koonin, V.M. Dixit, De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling, Nature 430 (2004) 694–699.
Please cite this article as: I. Matsumoto, et al., Regulatory roles of tumor necrosis factor alpha-induced proteins (TNFAIPs) 3 and 9 in arthritis, Clin. Immunol. (2014), http://dx.doi.org/10.1016/j.clim.2014.03.015
242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 Q16 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309
6 [19] T.G. Grunewald, H. Bach, A. Cossarizza, I. Matsumoto, The STEAP protein family: versatile oxidoreductases and targets for cancer immunotherapy with overlapping and distinct cellular functions, Biol. Cell. 104 (2012) 641–657. [20] C.G. Korkmanz, K.S. Korkmanz, P. Kurys, C. Elbi, L. Wang, T.I. Klokk, et al., Molecular cloning and characterization of STAMP2, an androgen-regulated six transmembrane protein that is overexpressed in prostate cancer, Oncogene 24 (2005) 4934–4945. [21] G.H. Gauss, M.D. Kleven, A.K. Sendamarai, M.D. Fleming, C.M. Lawrence, The crystal structure of six-transmembrane epithelial antigen of the prostate 4 (STEAP4), a ferri/cuprireductase, suggests a novel interdomain flavin-binding site, J. Biol. Chem. 288 (2013) 20668–20682. [22] Y. Tanaka, I. Matsumoto, K. Iwanami, A. Inoue, R. Minami, N. Umeda, et al., Six-transmembrane epithelial antigen of prostate4 (STEAP4) is a tumor necrosis factor alpha-induced protein that regulates IL-6, IL-8, and cell proliferation in synovium from patients with rheumatoid arthritis, Mod. Rheumatol. 22 (2012) 128–136. [23] Y. Tanaka, I. Matsumoto, K. Iwanami, A. Inoue, N. Umeda, Y. Tanaka, et al., Six-transmembrane epithelial antigen of
[24]
[25]
N C O
R
R
E
C
T
E
D
P
R O
[27]
O
F
[26]
prostate4 (STEAP4) is expressed on monocytes/neutrophils, and is regulated by TNF antagonist in patients with rheumatoid arthritis, Clin. Exp. Rheumatol. 30 (2012) 99–102. I. Matsumoto, H. Zhang, T. Yasukochi, K. Iwanami, Y. Tanaka, A. Inoue, et al., Therapeutic effects of antibodies to tumor necrosis factor-alpha, interleukin-6 and cytotoxic T-lymphocyte antigen 4 immunoglobulin in mice with glucose-6-phosphate isomerase induced arthritis, Arthritis Res. Ther. 10 (2008) R66. K. Iwanami, I. Matsumoto, Y. Tanaka-Watanabe, A. Inoue, M. Mihara, Y. Ohsugi, et al., Crucial role of the interleukin-6/ interleukin-17 cytokine axis in the induction of arthritis by glucose-6-phosphate isomerase, Arthritis Rheum. 58 (2008) 754–763. T. Wangensteen, H. Akselsen, J. Holmen, D. Undlien, L. Retterstøl, A common haplotype in NAPEPLD is associated with severe obesity in a Norwegian population-based cohort (the HUNT study), Obesity (Silver Spring) 19 (2011) 612–617. Y.Y. Guo, N.F. Li, L. Zhou, X.G. Yao, H.M. Wang, J.H. Zhang, et al., A common variation within the STEAP4 gene exons is associated with obesity in Uygur general population, Chin. Med. J. (Engl.) 124 (2011) 2096–2100.
U
310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 354
I. Matsumoto et al.
Please cite this article as: I. Matsumoto, et al., Regulatory roles of tumor necrosis factor alpha-induced proteins (TNFAIPs) 3 and 9 in arthritis, Clin. Immunol. (2014), http://dx.doi.org/10.1016/j.clim.2014.03.015
332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353
