ABSTRACT: 

IL-35 belongs to the IL-12 family of cytokines that are involved in immune-regulation and homeostasis. It generally features as a heterodimeric cytokine composed of IL-12p35 and EBV-induced gene 3, mainly secreted by regulatory T cells and B cells within the human body. Therefore, IL-35 is known to have enormous immune-suppressive abilities. This paper thus provides the existing insights over the biochemistry and pathophysiology of IL-35 concerning inflammation, microbial infections, carcinogenesis, as well as autoimmune disorders, meanwhile intending to identify lacunae and suggest prospective lines of research.

REFERENCES :

1) Abel, Alex M.., Yang, Chao., Thakar, M.., & Malarkannan, S. (2018). Natural Killer Cells: Development, Maturation, and Clinical Utilization. Frontiers in Immunology, 9. http://doi.org/10.3389/fimmu.2018.01869
2) Behzadi, P.., Behzadi, E.., & Ranjbar, R. (2016). IL-12 Family Cytokines: General Characteristics, Pathogenic Microorganisms, Receptors, and Signalling Pathways. Acta microbiologica et immunologica Hungarica, 63 1, 1-25. http://doi.org/10.1556/030.63.2016.1.1
3) Bettini, Maria., Castellaw, A.., Lennon, G.., Burton, A.., & Vignali, D. (2012). Prevention of Autoimmune Diabetes by Ectopic Pancreatic β-Cell Expression of Interleukin-35. Diabetes, 61, 1519 – 1526. http://doi.org/10.2337/db11-0784
4) Cheng, Shu-Chen., Huang, Wen-Chung., Pang, Jong-Hwei S.., Wu, Yi-Hong., & Cheng, Ching-Yi. (2019). Quercetin Inhibits the Production of IL-1β-Induced Inflammatory Cytokines and Chemokines in ARPE-19 Cells via the MAPK and NF-κB Signaling Pathways. International Journal of Molecular Sciences, 20. http://doi.org/10.3390/ijms20122957
5) Choi, Jinjung., Leung, P.., Bowlus, C.., & Gershwin, M. (2015). IL-35 and Autoimmunity: a Comprehensive Perspective. Clinical Reviews in Allergy & Immunology, 49, 327-332. http://doi.org/10.1007/s12016-015-8468-9
6) Collison, L.., Delgoffe, Greg M.., Guy, Clifford S.., Vignali, K.., Chaturvedi, Vandana., Fairweather, D.., Satoskar, A.., Garcia, K.., Hunter, C.., Drake, C.., Murray, P.., & Vignali, D. (2012). The composition and signaling of the IL-35 receptor are unconventional. Nature Immunology, 13, 290-299. http://doi.org/10.1038/ni.2227
7) Dambuza, I.., He, Chang., Choi, J. K.., Yu, C.., Wang, R.., Mattapallil, M.., Wingfield, P.., Caspi, R.., & Egwuagu, C. (2017). IL-12p35 induces expansion of IL-10 and IL-35-expressing regulatory B cells and ameliorates autoimmune disease. Nature Communications, 8. http://doi.org/10.1038/s41467-017-00838-4
8) Gomes-Giacoia, Evan., Miyake, M.., Goodison, S.., Sriharan, Aravindhan., Zhang, Ge., You, Lijing., Egan, J.., Rhode, P.., Parker, A.., Chai, K.., Wong, H.., & Rosser, C. (2014). Intravesical ALT-803 and BCG Treatment Reduces Tumor Burden in a Carcinogen Induced Bladder Cancer Rat Model; a Role for Cytokine Production and NK Cell Expansion. PLoS ONE, 9. http://doi.org/10.1371/journal.pone.0096705
9) Huang, R-L., Yuan, Y.., Tu, J.., Zou, G-M., & Li, Q. (2014). Opposing TNF-α/IL-1β- and BMP-2-activated MAPK signaling pathways converge on Runx2 to regulate BMP-2-induced osteoblastic differentiation. Cell Death & Disease, 5. http://doi.org/10.1038/cddis.2014.101
10) Jiang, Mei., Wang, Hairong., Jin, Mingming., Yang, Xuelian., Ji, Haifeng., Jiang, Yufeng., Zhang, Hanwen., Wu, Feifei., Wu, Guolu., Lai, Xiaoyin., Cai, Liying., Hu, Rongguo., Xu, Limin., & Li, Longxuan. (2018). Exosomes from MiR-30d-5p-ADSCs Reverse Acute Ischemic Stroke-Induced, Autophagy-Mediated Brain Injury by Promoting M2 Microglial/Macrophage Polarization. Cellular Physiology and Biochemistry, 47, 86878. http://doi.org/10.1159/000490078
11) Khan, Shaheen., Khan, S.., Luo, Xin., Fattah, F.., Saltarski, Jessica M.., Gloria-McCutchen, Yvonne., Lu, Rong., Xie, Yang., Li, Quanzhen., Wakeland, E.., & Gerber, D. (2018). Immune dysregulation in cancer patients developing immune-related adverse events. British Journal of Cancer, 120, 63 – 68. http://doi.org/10.1038/s41416-018-0155-1
12) Langhans, B.., Nischalke, H.., Krämer, B.., Dold, L.., Lutz, P.., Mohr, R.., Vogt, A.., Toma, M.., Eis-Hübinger, A.., Nattermann, J.., Strassburg, C.., Gonzalez-Carmona, M.., & Spengler, U. (2019). Role of regulatory T cells and checkpoint inhibition in hepatocellular carcinoma. Cancer Immunology, Immunotherapy, 68, 2055 – 2066http://doi.org/10.1007/s00262-019-02427-4
13) Li, Xinyuan., Mai, J.., Virtue, A.., Yin, Ying-Xuan., Gong, Ren., Sha, Xiaojin., Gutchigian, Stefanie., Frisch, A.., Hodge, I.., Jiang, Xiaohua., Wang, Hong., & Yang, Xiaofeng. (2012). IL-35 Is a Novel Responsive Anti-inflammatory Cytokine — A New System of Categorizing Anti-inflammatory Cytokines. PLoS ONE, 7 . http://doi.org/10.1371/journal.pone.0033628
14) Matsushita, T.., Hamaguchi, Y.., Hasegawa, M.., Takehara, K.., & Fujimoto, M.. (2016). Decreased levels of regulatory B cells in patients with systemic sclerosis: association with autoantibody production and disease activity.. Rheumatology , 55 2 , 263-7 . http://doi.org/10.1093/rheumatology/kev331
15) Mirlekar, B.. (2022). Tumor promoting roles of IL-10, TGF-β, IL-4, and IL-35: Its implications in cancer immunotherapy. SAGE Open Medicine , 10 . http://doi.org/10.1177/20503121211069012
16) Naclerio, R.., Meier, H.., Kagey-sobotka, A.., Adkinson, N.., Meyers, D.., Norman, P.., & Lichtenstein, L.. (2015). Mediator release after nasal airway challenge with allergen.. The American review of respiratory disease , 134 5 , 1102 . http://doi.org/10.1164/ARRD.1986.134.5.1102
17) Pastrana, Jahaira Lopez., Sha, Xiaojin., Virtue, A.., Mai, J.., Cueto, Ramón., Lee, In Ae., Wang, Hong., & Yang, Xiaofeng. (2012). Regulatory T cells and Atherosclerosis.. Journal of clinical & experimental cardiology , 2012 Suppl 12 , 2 . http://doi.org/10.4172/2155-9880.S12-002
18) Sánchez-Vega, F.., Mina, Marco., Armenia, J.., Chatila, W.., Luna, Augustin., La, Konnor C.., Dimitriadoy, Sofia G.., Liu, David L.., Kantheti, Havish S.., Saghafinia, S.., Chakravarty, D.., Daian, Foysal., Gao, Qingsong., Bailey, Matthew H.., Liang, Wen-Wei., Foltz, S.., Shmulevich, I.., Ding, L.., Heins, Zachary J.., Ochoa, Angelica., Gross, Benjamin E.., Gao, Jianjiong., Zhang, Hongxin., Kundra, Ritika., Kandoth, C.., Bahceci, Istemi., Dervishi, L.., Dogrusoz, U.., Zhou, Wanding., Shen, Hui., Laird, P.., Way, G.., Greene, C.., Liang, Han., Xiao, Yonghong., Wang, Chen., Iavarone, A.., Berger, A.., Bivona, T.., Lazar, A.., Hammer, G.., Giordano, T.., Kwong, L.., McArthur, G.., Huang, Chenfei., Tward, A.., Frederick, M.., McCormick, F.., Meyerson, M.., Allen, E.., Cherniack, A.., Ciriello, G.., Sander, C.., Schultz, N.., Caesar-Johnson, Samantha J.., Demchok, John A.., Felau, Ina., Kasapi, M.., Ferguson, M.., Hutter, C.., Sofia, H.., Tarnuzzer, R.., Wang, Zhining., Yang, Liming., Zenklusen, J.., Zhang, J.., Chudamani, Sudha., Liu, Jia., Lolla, Laxmi., Naresh, R.., Pihl, T.., Sun, Qiang., Wan, Yunhu., Wu, Ye., Cho, Juok., DeFreitas, T.., Frazer, S.., Gehlenborg, Nils., Getz, G.., Heiman, David I., Kim, Jaegil., Lawrence, M.., Lin, Pei., Meier, S.., Noble, M.., Saksena, G.., Voet, Douglas., Zhang, Hailei., Bernard, Brady., Chambwe, N.., Dhankani, Varsha., Knijnenburg, T.., Kramer, R.., Leinonen, Kalle., Liu, Yuexin., Miller, Michael., Reynolds, Sheila M.., Thorsson, V.., Zhang, Wei., Akbani, Rehan., Broom, B.., Hegde, A.., Ju, Z.., Kanchi, R.., Korkut, Anil., Li, Jun., Ling, Shiyun., Liu, Wenbin., Lu, Yiling., Mills, G.., Ng, Kwok-Shing., Rao, A.., Ryan, Michael J.., Wang, Jing., Weinstein, J.., Zhang, Jiexin., Abeshouse, Adam., Bruijn, I.., Gross, Benjamin E.., Heins, Zachary J.., La, Konnor C.., Ladanyi, M.., Nissan, Moriah G.., Phillips, Sarah M.., Reznik, E.., Sheridan, R.., Sumer, S. O.., Sun, Yichao., Taylor, B.., Wang, Jioajiao., Anur, Pavana., Peto, Myron., Spellman, P.., Benz, C.., Stuart, Joshua M.., Wong, Christopher K.., Yau, C.., Hayes, D.., Parker, J.., Wilkerson, M.., Ally, Adrian., Balasundaram, M.., Bowlby, R.., Brooks, Denise., Carlsen, R.., Chuah, E.., Dhalla, Noreen., Holt, Robert W.., Jones, Steven J. M.., Kasaian, K.., Lee, Darlene., Ma, Yussanne., Marra, M.., Mayo, Michael., Moore, Richard A.., Mungall, A.., Mungall, K.., Robertson, A. G.., Sadeghi, S.., Schein, J.., Sipahimalani, Payal., Tam, Angela., Thiessen, N.., Tse, Kane., Wong, Tina., Berger, Ashton C.., Beroukhim, R.., Cibulskis, C.., Gabriel, S.., Gao, G.., Ha, G.., Schumacher, S.., Shih, J.., Kucherlapati, M.., Kucherlapati, R.., Baylin, Stephen., Cope, L.., Danilova, Ludmila V.., Bootwalla, Moiz., Lai, Phillip H.., Maglinte, D.., Berg, D. V.., Weisenberger, D.., Auman, J.., Balu, S.., Bodenheimer, T.., Fan, C.., Hoadley, K.., Hoyle, A.., Jefferys, S.., Jones, Corbin D.., Meng, S.., Mieczkowski, P.., Mose, Lisle E.., Perou, Amy H.., Perou, C.., Roach, J.., Shi, Yan., Simons, J.., Skelly, Tara J.., Soloway, Matthew G.., Tan, Donghui., Veluvolu, Umadevi., Fan, Huihui., Hinoue, T.., Bellair, Michelle., Chang, K.., Covington, K.., Creighton, C.., Dinh, H.., Doddapaneni, H.., Donehower, L.., Drummond, J.., Gibbs, R.., Glenn, R.., Hale, Walker., Han, Yi., Hu, Jianhong., Korchina, V.., Lee, Sandy., Lewis, L.., Li, Wei., Liu, Xiuping., Morgan, M.., Morton, Donna., Muzny, D.., Santibanez, J.., Sheth, Margi., Shinbrot, E.., Wang, Linghua., Wang, Min., Wheeler, D.., Xi, Liu., Zhao, Fengmei., Hess, J.., Appelbaum, Elizabeth L.., Bailey, Matthew H.., Cordes, M.., Fronick, C.., Fulton, L.., Fulton, R.., Mardis, E.., McLellan, M.., Miller, Christopher A.., Schmidt, Heather K.., Wilson, R.., Crain, D.., Curley, Erin E.., Gardner, J.., Lau, Kevin R., Mallery, D.., Morris, S.., Paulauskis, J.., Penny, R.., Shelton, C.., Shelton, T.., Sherman, M.., Thompson, E.., Yena, P.., Bowen, Jay., Gastier-Foster, J.., Gerken, M.., Leraas, K.., Lichtenberg, T.., Ramirez, N.., Wise, L.., Zmuda, E.., Corcoran, N.., Costello, T.., Hovens, C.., Carvalho, A.., Carvalho, A. D.., Fregnani, José H.., Longatto-Filho, A.., Reis, R.., Scapulatempo-Neto, C.., Silveira, H. C.., Vidal, D. O.., Burnette, Andrew., Eschbacher, J.., Hermes, B.., Noss, Ardene., Singh, Rosy., Anderson, Matthew L.., Castro, Patricia D.., Ittmann, M.., Huntsman, D.., Kohl, B.., Le, X.., Thorp, Richard A.., Andry, C.., Duffy, Elizabeth R.., Lyadov, V.., Paklina, O.., Setdikova, G.., Shabunin, A.., Tavobilov, M.., McPherson, C.., Warnick, R.., Berkowitz, R.., Cramer, Daniel., Feltmate, C.., Horowitz, N.., Kibel, A.., Muto, M.., Raut, C.., Malykh, A.., Barnholtz-Sloan, J.., Barrett, Wendi., Devine, K.., Fulop, J.., Ostrom, Q.., Shimmel, K.., Wolinsky, Yingli., Sloan, A.., Rose, A. D.., Giuliante, F.., Goodman, M.., Karlan, B.., Hagedorn, C.., Eckman, J.., Harr, Jodi., Myers, J.., Tucker, Kelinda., Zach, L. A.., Deyarmin, B.., Hu, Hai., Kvecher, L.., Larson, C.., Mural, R.., Somiari, S.., Vicha, A.., Zelinka, T.., Bennett, Joseph., Iacocca, M.., Rabeno, B.., Swanson, P.., Latour, M.., Lacombe, L.., Têtu, B.., Bergeron, A.., McGraw, Mary., Staugaitis, S.., Chabot, J.., Hibshoosh, H.., Sepulveda, Antonia R.., Su, Tao., Wang, Timothy C.., Potapova, O.., Voronina, Olga., Desjardins, L.., Mariani, O.., Roman-Roman, S.., Sastre, X.., Stern, M.., Cheng, F.., Signoretti, S.., Berchuck, A.., Bigner, D.., Lipp, E.., Marks, J.., McCall, S.., McLendon, R.., Secord, A.., Sharp, A.., Behera, M.., Brat, D.., Chen, Amy Y.., Delman, K.., Force, S.., Khuri, F.., Magliocca, K.., Maithel, S.., Olson, J.., Owonikoko, T.., Pickens, A.., Ramalingam, S.., Shin, Dong-Myung., Sica, G.., Meir, Erwin G. Van., Zhang, Hongzhen., Eijckenboom, Wil., Gillis, A.., Korpershoek, E.., Looijenga, L.., Oosterhuis, W.., Stoop, H.., Kessel, K. V.., Zwarthoff, E.., Calatozzolo, C.., Cuppini, L.., Cuzzubbo, S.., DiMeco, F.., Finocchiaro, G.., Mattei, L.., Perin, A.., Pollo, B.., Chen, Chu., Houck, J.., Lohavanichbutr, Pawadee., Hartmann, A.., Stoehr, C.., Stoehr, R.., Taubert, H.., Wach, S.., Wullich, B.., Kycler, W.., Murawa, D.., Wiznerowicz, M.., Chung, K.., Edenfield, W.., Martin, Julie M., Baudin, E.., Bubley, G.., Bueno, R.., Rienzo, A.., Richards, W.., Kalkanis, S.., Mikkelsen, T.., Noushmehr, H.., Scarpace, L.., Girard, N.., Aymerich, M.., Campo, E.., Giné, E.., Guillermo, A.., Bang, N. V.., Hanh, Phan Thi Hong., Phu, Bui Duc., Tang, Yufang., Colman, H.., Evason, K.., Dottino, P.., Martignetti, J.., Gabra, H.., Juhl, H.., Akeredolu, Teniola., Stepa, Serghei., Hoon, D.., Ahn, Keun-Young., Kang, K.., Beuschlein, F.., Breggia, A.., Birrer, M.., Bell, D.., Borad, M.., Bryce, A.., Castle, Erik., Chandan, V.., Cheville, J.., Copland, J.., Farnell, M.., Flotte, T.., Giama, N.., Ho, T.., Kendrick, Michael J.., Kocher, J.., Kopp, Karla J.., Moser, C.., Nagorney, D.., O’Brien, D.., O’neill, B.., Patel, T.., Petersen, G.., Que, F.., Rivera, M.., Roberts, L.., Smallridge, R.., Smyrk, T.., Stanton, M.., Thompson, R.., Torbenson, M.., Yang, J. D.., Zhang, Lizhi., Brimo, F.., Ajani, J.., Gonzalez, Ana Maria Angulo., Behrens, C.., Bondaruk, J.., Broaddus, R.., Czerniak, B.., Esmaeli, B.., Fujimoto, J.., Gershenwald, J.., Guo, C.., Logothetis, Christopher., Meric-Bernstam, F.., Morán, C.., Ramondetta, L.., Rice, D.., Sood, A.., Tamboli, P.., Thompson, T.., Troncoso, P.., Tsao, A.., Wistuba, I.., Carter, Candace D.., Haydu, L.., Hersey, P.., & Jakrot, V.. (2018). Oncogenic Signaling Pathways in The Cancer Genome Atlas.. Cell , 173 2 , 321-337.e10 . http://doi.org/10.1016/j.cell.2018.03.035
19) Sawant, Deepali V.., Hamilton, K.., & Vignali, D.. (2015). Interleukin-35: Expanding Its Job Profile.. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research , 35 7 , 499-512 . http://doi.org/10.1089/jir.2015.0015
20) Shen, Ping., Roch, T.., Lampropoulou, Vicky., O’Connor, R.., Stervbo, U.., Hilgenberg, Ellen., Ries, S.., Dang, V.., Jaimes, Y.., Daridon, C.., Li, Rui., Jouneau, L.., Boudinot, P.., Wilantri, S.., Sakwa, Imme., Miyazaki, Y.., Leech, M.., McPherson, Rhoanne C.., Wirtz, S.., Neurath, M.., Hoehlig, Kai., Meinl, E.., Grützkau, A.., Grün, J.., Horn, Katharina., Kühl, A.., Dörner, T.., Bar-Or, A.., Kaufmann, S.., Anderton, S.., & Fillatreau, S.. (2014). IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature , 507 , 366-370 . http://doi.org/10.1038/nature12979
21) Tefferi, A.., Vaidya, R.., Caramazza, D.., Finke, C.., Lasho, T.., & Pardanani, A.. (2011). Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study.. Journal of clinical oncology : official journal of the American Society of Clinical Oncology , 29 10 , 1356-63 . http://doi.org/10.1200/JCO.2010.32.9490
22) Wang, Xiaoqian., Wei, Yinxiang., Xiao, He., Liu, Xiaoling., Zhang, Yu., Han, G.., Chen, Guojiang., Hou, C.., Ma, N.., Shen, B.., Li, Yan., Egwuagu, C.., & Wang, R.. (2016). A novel IL‐23p19/Ebi3 (IL‐39) cytokine mediates inflammation in Lupus‐like mice. European Journal of Immunology , 46 . http://doi.org/10.1002/eji.201546095
23) Yeung, Yiu To., Aziz, F.., Guerrero-Castilla, Angélica., & Arguelles, Sandro. (2018). Signaling Pathways in Inflammation and Anti-inflammatory Therapies.. Current pharmaceutical design , 24 14 , 1449-1484 . http://doi.org/10.2174/1381612824666180327165604
24) Yoshida, G. J.. (2020). Regulation of heterogeneous cancer-associated fibroblasts: the molecular pathology of activated signaling pathways. Journal of Experimental & Clinical Cancer Research : CR , 39 . http://doi.org/10.1186/s13046-020-01611-0
25) Zegeye, Mulugeta M.., Lindkvist, Madelene., Fälker, Knut., Kumawat, A.., Paramel, G.., Grenegård, M.., Sirsjö, A.., & Ljungberg, L.. (2018). Activation of the JAK/STAT3 and PI3K/AKT pathways are crucial for IL-6 trans-signaling-mediated pro-inflammatory response in human vascular endothelial cells. Cell Communication and Signaling : CCS , 16 . http://doi.org/10.1186/s12964-018-0268-4
26) Zhang, Xiao-hui., Zeng, Yuanyuan., Qu, Qiu-Xia., Zhu, Jianjie., Liu, Zeyi., Ning, Weiwei., Zeng, Hui-chang., Zhang, Nan., Du, W.., Chen, Cheng., & Huang, Jian-an. (2017). PD-L1 induced by IFN-γ from tumor-associated macrophages via the JAK/STAT3 and PI3K/AKT signaling pathways promoted progression of lung cancer. International Journal of Clinical Oncology , 22 , 1026-1033 . http://doi.org/10.1007/s10147-017-1161-7
27) Zhao, Huakan., Wu, Lei., Yan, Guifang., Chen, Yu., Zhou, Mingyue., Wu, Yongzhong., & Li, Yongsheng. (2021). Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduction and Targeted Therapy , 6 . http://doi.org/10.1038/s41392-021-00658-5
28) Zhu, Y.., Brown, Jonathan., Sag, Duygu., Zhang, Lihua., & Suttles, J.. (2015). Adenosine 5′-Monophosphate–Activated Protein Kinase Regulates IL-10–Mediated Anti-Inflammatory Signaling Pathways in Macrophages. The Journal of Immunology , 194 , 584 – 594 . http://doi.org/10.4049/jimmunol.1401024