肥胖是一種慢性發炎疾病，與胰島素抗性、心血管疾病以及非酒精性脂肪肝疾病的發生有密切關係。生活習慣、基因遺傳、飲食與代謝失調都可能造成肥胖。在肥胖發展過程中，免疫細胞會浸潤到脂肪組織中，其中以單核細胞以及巨噬細胞為主要的族群，這些細胞會分泌許多促發炎細胞激素，包括TNF-α、 IL-1β、 IL-6和IL-8,進而引起脂肪組織的慢性發炎反應。因此在肥胖的發炎微環境中，脂肪細胞與巨噬細胞間之交互作用是十分關鍵。介白素二十九 (Interleukin-29, IL-29)是第三型干擾素(interferon)家族的一員，透過IL-28R1和IL-10R2這對接受器來傳遞訊號啟動生物功能。IL-29在宿主對抗微生物入侵中具有重要作用，在感染病毒的細胞中其表現量顯著上升。過去文獻得知巨噬細胞、樹突細胞、週邊血液單核細胞都會分泌IL-29。然而，IL-29是否參與在肥胖的慢性發炎中是未知的。首先，我們發現肥胖患者的血清中可偵測高量的IL-29，且在肥胖患者的脂肪組織表現IL-29。在人類脂肪細胞株(SGBS cells)的成熟過程中會大量的表達IL-28R1和IL-10R2這對接受器，因此可作為IL-29的目標細胞。實驗發現，IL-29會促使脂肪細胞表達高量的IL-1與IL-8。同時，IL-29會調節脂肪細胞的葡萄糖轉運蛋白(Glucose transporter type 4; GLUT4)，進而抑制胰島素所誘導之葡萄糖的攝入。巨噬細胞在經由IFN-α和LPS刺激下能表現IL-29。實驗進一步發現脂肪細胞及巨噬細胞共同培養會誘發IL-6、IL-8以及MCP-1的產生，而加入抗IL-29單株抗體的處理，可以顯著地減少這些促發炎細胞激素的產生。最後我們發現IL-29會促進THP-1單核細胞的趨化作用。這些結果推論，巨噬細胞表現IL-29，可作用在脂肪細胞上，並促使脂肪細胞的發炎反應以及降低葡萄糖的攝入，因此IL-29具有調節胰島素抗性的作用。綜合上述結果，我們認為IL-29在脂肪細胞及巨噬細胞的交互作用扮演著促進發炎反應的角色。

Obesity is a chronic inflammatory disease that is closely related to the development of insulin resistance, cardiovascular disease and nonalcoholic fatty liver disease. In the progression of obesity, immune cells are infiltrated into adipose tissue. Most are monocytes and macrophages. These cells secrete various inflammatory factors, including TNF-α, IL-1β, IL-6, and IL-8 and then cause chronic inflammation of adipose tissue. Therefore, adipocytes and macrophages interaction plays a critical role in the inflammatory environment of obesity. Interleukin-29 (IL-29), a member of type 3 interferon family, signals through a heterodimer receptor complex of IL-28R1 and IL-10R2 to initiate biological functions. IL-29 plays an important role in the host against microbes and its gene is highly upregulated in cells infected with viruses. Several studies reported that macrophages, dendritic cells, and peripheral blood mononuclear cells (PBMC) expressed IL-29. However, little is known whether IL-29 is involved in obesity. In this study, we found that serum IL-29 level was significantly higher in obese patients compared with healthy controls, and IL-29 was also detected in obese adipose tissue. IL-28R1 and IL-10R2 were expressed in mature human SGBS adipocytes which could serve as target cells of IL-29. IL-29 upregulated IL-1β and IL-8 expression in mature SGBS adipocytes. In addition, IL-29 regulated glucose transporter 4 (GLUT4) expression and inhibited insulin-stimulated glucose intake. Macrophages expressed IL-29 after IFN-α and LPS stimulation. Using an in vitro co-culture system of macrophages and adipocytes to mimic an obese microenvironment, we found that inhibition of IL-29 with a neutralizing antibody reduced the production of inflammatory cytokines such as IL-6, IL-8, and MCP-1. Finally, we found that IL-29 significantly promoted cell migration of THP-1 monocytes. These findings indicated that IL-29 is an important regulator for contributing adipose tissue inflammation, adipose tissue monocyte chemotaxis, and insulin-mediated glucose uptake. Therefore, we have identified a critical role of IL-29 in adipocyte-macrophage crosstalk and we conclude that IL-29 may be a new target for treating obesity-induced metabolic inflammation.

1. Nguyen, D.M. and H.B. El-Serag, The Epidemiology of Obesity. Gastroenterology clinics of North America, 2010. 39(1): p. 1-7.
2. <Sugars and Obesity.pdf>.
3. Maffetone, P.B., I. Rivera-Dominguez, and P.B. Laursen, Overfat and Underfat: New Terms and Definitions Long Overdue. Frontiers in Public Health, 2016. 4: p. 279.
4. Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants. Lancet, 2016. 387(10026): p. 1377-1396.
5. Subramanian, V. and A.W. Ferrante, Jr., Obesity, inflammation, and macrophages. Nestle Nutr Workshop Ser Pediatr Program, 2009. 63: p. 151-9; discussion 159-62, 259-68.
6. Guilherme, A., et al., Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol, 2008. 9(5): p. 367-77.
7. Kim, J.B., Dynamic cross talk between metabolic organs in obesity and metabolic diseases. Exp Mol Med, 2016. 48: p. e214.
8. Kahn, B.B. and J.S. Flier, Obesity and insulin resistance. Journal of Clinical Investigation, 2000. 106(4): p. 473-481.
9. Hotamisligil, G.S., Inflammation, metaflammation and immunometabolic disorders. Nature, 2017. 542(7640): p. 177-185.
10. Hotamisligil, G., N. Shargill, and B. Spiegelman, Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science, 1993. 259(5091): p. 87-91.
11. Vandanmagsar, B., et al., The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med, 2011. 17(2): p. 179-188.
12. Moschen, A.R., et al., Adipose and liver expression of interleukin (IL)-1 family members in morbid obesity and effects of weight loss. Mol Med, 2011. 17(7-8): p. 840-5.
13. Roytblat, L., et al., Raised Interleukin-6 Levels in Obese Patients. Obesity Research, 2000. 8(9): p. 673-675.
14. Kern, P.A., et al., Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. American Journal of Physiology - Endocrinology And Metabolism, 2001. 280(5): p. E745-E751.
15. Eder, K., et al., The major inflammatory mediator interleukin-6 and obesity. Inflammation Research, 2009. 58(11): p. 727.
16. Panee, J., Monocyte Chemoattractant Protein 1 (MCP-1) in obesity and diabetes. Cytokine, 2012. 60(1): p. 1-12.
17. Kim, C.S., et al., Circulating levels of MCP-1 and IL-8 are elevated in human obese subjects and associated with obesity-related parameters. Int J Obes, 2006. 30(9): p. 1347-1355.
18. Lackey, D.E. and J.M. Olefsky, Regulation of metabolism by the innate immune system. Nat Rev Endocrinol, 2016. 12(1): p. 15-28.
19. Sell, H., C. Habich, and J. Eckel, Adaptive immunity in obesity and insulin resistance. Nat Rev Endocrinol, 2012. 8(12): p. 709-716.
20. Lumeng, C.N., Innate Immune Activation in Obesity. Molecular aspects of medicine, 2013. 34(1): p. 12-29.
21. Osborn, O. and J.M. Olefsky, The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med, 2012. 18(3): p. 363-374.
22. McArdle, M., et al., Mechanisms of Obesity-Induced Inflammation and Insulin Resistance: Insights into the Emerging Role of Nutritional Strategies. Frontiers in Endocrinology, 2013. 4(52).
23. Dalmas, E., K. Clément, and M. Guerre-Millo, Defining macrophage phenotype and function in adipose tissue. Trends in Immunology. 32(7): p. 307-314.
24. Choe, S.S., et al., Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders. Frontiers in Endocrinology, 2016. 7(30).
25. Sheppard, P., et al., IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol, 2003. 4(1): p. 63-8.
26. Kotenko, S.V., et al., IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol, 2003. 4(1): p. 69-77.
27. Xu, L., et al., Interleukin-29 induces receptor activator of NF-kappaB ligand expression in fibroblast-like synoviocytes via MAPK signaling pathways. Int J Rheum Dis, 2015. 18(8): p. 842-9.
28. Wolk, K., et al., Maturing dendritic cells are an important source of IL-29 and IL-20 that may cooperatively increase the innate immunity of keratinocytes. J Leukoc Biol, 2008. 83(5): p. 1181-93.
29. Wolk, K., et al., IL-29 is produced by T(H)17 cells and mediates the cutaneous antiviral competence in psoriasis. Sci Transl Med, 2013. 5(204): p. 204ra129.
30. Siren, J., et al., IFN-alpha regulates TLR-dependent gene expression of IFN-alpha, IFN-beta, IL-28, and IL-29. J Immunol, 2005. 174(4): p. 1932-7.
31. Kelm, N.E., et al., The role of IL-29 in immunity and cancer. Critical Reviews in Oncology/Hematology, 2016. 106: p. 91-98.
32. Benson, R.A., et al., Cellular imaging in rheumatic diseases. Nat Rev Rheumatol, 2015. advance online publication.
33. Smolen, J.S., D. Aletaha, and K. Redlich, The pathogenesis of rheumatoid arthritis: new insights from old clinical data? Nat Rev Rheumatol, 2012. 8(4): p. 235-243.
34. McInnes, I.B. and G. Schett, Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol, 2007. 7(6): p. 429-442.
35. Wang, F., et al., Interleukin-29 modulates proinflammatory cytokine production in synovial inflammation of rheumatoid arthritis. Arthritis Res Ther, 2012. 14(5): p. R228.
36. Xu, L., et al., IL-29 enhances Toll-like receptor-mediated IL-6 and IL-8 production by the synovial fibroblasts from rheumatoid arthritis patients. Arthritis Res Ther, 2013. 15(5): p. R170.
37. Xu, L., et al., Interleukin-29 Enhances Synovial Inflammation and Cartilage Degradation in Osteoarthritis. Mediators Inflamm, 2016. 2016: p. 9631510.
38. Finn, P.W. and T.D. Bigby, Innate Immunity and Asthma. Proceedings of the American Thoracic Society, 2009. 6(3): p. 260-265.
39. Holtzman, M.J., Asthma as a chronic disease of the innate and adaptive immune systems responding to viruses and allergens. The Journal of Clinical Investigation, 2012. 122(8): p. 2741-2748.
40. Holgate, S.T., Innate and adaptive immune responses in asthma. Nat Med, 2012. 18(5): p. 673-683.
41. Liao, S.-C., et al., IL-19 Induced Th2 Cytokines and Was Up-Regulated in Asthma Patients. The Journal of Immunology, 2004. 173(11): p. 6712-6718.
42. Deckers, J., F. Branco Madeira, and H. Hammad, Innate immune cells in asthma. Trends in Immunology. 34(11): p. 540-547.
43. He, S., et al., CD14+ cell-derived IL-29 modulates proinflammatory cytokine production in patients with allergic airway inflammation. Allergy, 2011. 66(2): p. 238-46.
44. Li, Y., et al., Adenovirus expressing IFN-lambda1 (IL-29) attenuates allergic airway inflammation and airway hyperreactivity in experimental asthma. Int Immunopharmacol, 2014. 21(1): p. 156-62.
45. Koch, S. and S. Finotto, Role of Interferon-lambda in Allergic Asthma. J Innate Immun, 2015. 7(3): p. 224-30.
46. Hansel, T.T., et al., A Comprehensive Evaluation of Nasal and Bronchial Cytokines and Chemokines Following Experimental Rhinovirus Infection in Allergic Asthma: Increased Interferons (IFN-gamma and IFN-lambda) and Type 2 Inflammation (IL-5 and IL-13). EBioMedicine, 2017. 19: p. 128-138.
47. Weisberg, S.P., et al., Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest, 2003. 112(12): p. 1796-808.
48. Fischer-Posovszky, P., et al., Human SGBS Cells – a Unique Tool for Studies of Human Fat Cell Biology. Obesity Facts, 2008. 1(4): p. 184-189.
49. Hammond, M.E., et al., IL-8 induces neutrophil chemotaxis predominantly via type I IL-8 receptors. The Journal of Immunology, 1995. 155(3): p. 1428-1433.
50. Turner, M.D., et al., Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2014. 1843(11): p. 2563-2582.
51. Bonecchi, R., et al., Induction of Functional IL-8 Receptors by IL-4 and IL-13 in Human Monocytes. The Journal of Immunology, 2000. 164(7): p. 3862-3869.
52. Keuper, M., et al., THP-1 Macrophages and SGBS Adipocytes – A New Human in vitro Model System of Inflamed Adipose Tissue. Frontiers in Endocrinology, 2011. 2: p. 89.
53. Khan, A. and J. Pessin, Insulin regulation of glucose uptake: a complex interplay of intracellular signalling pathways. Diabetologia, 2002. 45(11): p. 1475-1483.
54. Rotter, V., I. Nagaev, and U. Smith, Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem, 2003. 278(46): p. 45777-84.
55. Klop, B., J.W.F. Elte, and M. Castro Cabezas, Dyslipidemia in Obesity: Mechanisms and Potential Targets. Nutrients, 2013. 5(4): p. 1218-1240.
56. Jung, U. and M.-S. Choi, Obesity and Its Metabolic Complications: The Role of Adipokines and the Relationship between Obesity, Inflammation, Insulin Resistance, Dyslipidemia and Nonalcoholic Fatty Liver Disease. International Journal of Molecular Sciences, 2014. 15(4): p. 6184.
57. Boden, G., Obesity, insulin resistance and free fatty acids. Curr Opin Endocrinol Diabetes Obes, 2011. 18(2): p. 139-43.
58. Lumeng, C.N., J.L. Bodzin, and A.R. Saltiel, Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest, 2007. 117(1): p. 175-84.
59. Nguyen, M.T., et al., A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem, 2007. 282(48): p. 35279-92.
60. Hevener, A.L., et al., Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J Clin Invest, 2007. 117(6): p. 1658-69.
61. Boden, G., Free fatty acids-the link between obesity and insulin resistance. Endocr Pract, 2001. 7(1): p. 44-51.
62. Saleh, J., A.D. Sniderman, and K. Cianflone, Regulation of Plasma fatty acid metabolism. Clin Chim Acta, 1999. 286(1-2): p. 163-80.
63. Clemente-Postigo, M., et al., Adipose Tissue Gene Expression of Factors Related to Lipid Processing in Obesity. PLoS ONE, 2011. 6(9): p. e24783.
64. Klop, B., et al., A physician's guide for the management of hypertriglyceridemia: the etiology of hypertriglyceridemia determines treatment strategy. Panminerva Med, 2012. 54(2): p. 91-103.
65. Matsuki, T., et al., IL-1 Plays an Important Role in Lipid Metabolism by Regulating Insulin Levels under Physiological Conditions. The Journal of Experimental Medicine, 2003. 198(6): p. 877-888.
66. Glund, S. and A. Krook, Role of interleukin-6 signalling in glucose and lipid metabolism. Acta Physiol (Oxf), 2008. 192(1): p. 37-48.
67. Jovinge, S., et al., Evidence for a role of tumor necrosis factor alpha in disturbances of triglyceride and glucose metabolism predisposing to coronary heart disease. Metabolism, 1998. 47(1): p. 113-8.
68. Nov, O., et al., Interleukin-1β Regulates Fat-Liver Crosstalk in Obesity by Auto-Paracrine Modulation of Adipose Tissue Inflammation and Expandability. PLoS ONE, 2013. 8(1): p. e53626.
69. Kawakami, M., et al., Human recombinant TNF suppresses lipoprotein lipase activity and stimulates lipolysis in 3T3-L1 cells. J Biochem, 1987. 101(2): p. 331-8.
70. Hardardottir, I., et al., Effects of TNF, IL-1, and the combination of both cytokines on cholesterol metabolism in Syrian hamsters. Lymphokine Cytokine Res, 1994. 13(3): p. 161-6.
71. Greenberg, A.S., et al., Interleukin 6 reduces lipoprotein lipase activity in adipose tissue of mice in vivo and in 3T3-L1 adipocytes: a possible role for interleukin 6 in cancer cachexia. Cancer Res, 1992. 52(15): p. 4113-6.
72. Juge-Aubry, C.E., et al., Adipose tissue is a regulated source of interleukin-10. Cytokine, 2005. 29(6): p. 270-4.
73. Walter, M.R., The Molecular Basis of IL-10 Function: From Receptor Structure to the Onset of Signaling. Current topics in microbiology and immunology, 2014. 380: p. 191-212.