Helminth infection; Macrophage; Resistin-like molecule; T helper type 2; Toll-like Receptor 4
Abstract :
[en] The Resistin-Like Molecules (RELM) alpha, beta, and gamma and their namesake, resistin, share structural and sequence homology but exhibit significant diversity in expression and function within their mammalian host. RELM proteins are expressed in a wide range of diseases, such as: microbial infections (eg. bacterial and helminth), inflammatory diseases (eg. asthma, fibrosis) and metabolic disorders (eg. diabetes). While the expression pattern and molecular regulation of RELM proteins are well characterized, much controversy remains over their proposed functions, with evidence of host-protective and pathogenic roles. Moreover, the receptors for RELM proteins are unclear, although three receptors for resistin, decorin, adenylyl cyclase-associated protein 1 (CAP1), and Toll-like Receptor 4 (TLR4) have recently been proposed. In this review, we will first summarize the molecular regulation of the RELM gene family, including transcription regulation and tissue expression in humans and mouse disease models. Second, we will outline the function and receptor-mediated signaling associated with RELM proteins. Finally, we will discuss recent studies suggesting that, despite early misconceptions that these proteins are pathogenic, RELM proteins have a more nuanced and potentially beneficial role for the host in certain disease settings.
Teng, X., Li, D., Champion, H.C., Johns, R.A., FIZZ1/RELMα a Novel Hypoxia-Induced Mitogenic Factor in Lung With Vasoconstrictive and Angiogenic Properties. Circ. Res., 92(10), 2003, 1065.
Horsnell, W.G.C., Dewals, B.G., RELMs in the Realm of Helminths. Trends Parasitology 32:7 (2016), 512–514.
Gerstmayer, B., Küsters, D., Gebel, S., Müller, T., Van Miert, E., Hofmann, K., Bosio, A., Identification of RELMγ a novel resistin-like molecule with a distinct expression pattern☆. Genomics 81:6 (2003), 588–595.
Johns, R.A., Gao, L., Rafaels, N.M., Grant, A.V., Stockton-Porter, M.L., Watson, H.R., Beaty, T.H., Barnes, K.C., Polymorphisms in resistin and resistin-like beta predict bronchial hyperreactivity in human asthma. Proceed. Am. Thoracic Soc., 6(3), 2009 329 329.
Ghosh, S., Singh, A.K., Aruna, B., Mukhopadhyay, S., Ehtesham, N.Z., The genomic organization of mouse resistin reveals major differences from the human resistin: functional implications. Gene 305:1 (2003), 27–34.
He, W., Wang, M.-L., Jiang, H.-Q., Steppan, C.M., Shin, M.E., Thurnheer, M.C., Cebra, J.J., Lazar, M.A., Wu, G.D., Bacterial colonization leads to the colonic secretion of RELMβ/FIZZ2, a novel goblet cell-specific protein. Gastroenterology 125:5 (2003), 1388–1397.
Banerjee, R.R., Lazar, M.A., Dimerization of resistin and resistin-like molecules is determined by a single cysteine. J. Biol. Chem. 276:28 (2001), 25970–25973.
Chen, G., Wang, S.H., Jang, J.C., Odegaard, J.I., Nair, M.G., Comparison of RELM alpha and RELM beta single- and double-gene-deficient mice reveals that RELM alpha Expression dictates inflammation and worm expulsion in hookworm infection 2. Infect. Immun. 84:4 (2016), 1100–1111.
Shojima, N., Ogihara, T., Inukai, K., Fujishiro, M., Sakoda, H., Kushiyama, A., Katagiri, H., Anai, M., Ono, H., Fukushima, Y., Horike, N., Viana, A.Y.I., Uchijima, Y., Kurihara, H., Asano, T., Serum concentrations of resistin-like molecules β and γ are elevated in high-fat-fed and obese db/db mice, with increased production in the intestinal tract and bone marrow. Diabetologia 48:5 (2005), 984–992.
Jang, J.C., Chen, G., Wang, S.H., Barnes, M.A., Chung, J.I., Camberis, M., Le Gros, G., Cooper, P.J., Steel, C., Nutman, T.B., Lazar, M.A., Nair, M.G., Macrophage-derived human resistin is induced in multiple helminth infections and promotes inflammatory monocytes and increased parasite burden. PLoS Pathog., 11(1), 2015, e1004579.
Lee, M.-R., Shim, D., Yoon, J., Jang, H.S., Oh, S.-W., Suh, S.H., Choi, J.-H., Oh, G.T., Retnla overexpression attenuates allergic inflammation of the airway. PLOS ONE, 9(11), 2014, e112666.
Holcomb, I.N., Kabakoff, R.C., Chan, B., Baker, T.W., Gurney, A., Henzel, W., Nelson, C., Lowman, H.B., Wright, B.D., Skelton, N.J., Frantz, G.D., Tumas, D.B., Peale, F.V., Shelton, D.L., Hébert, C.C., FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J 19:15 (2000), 4046–4055.
Stütz, A.M., Pickart, L.A., Trifilieff, A., Baumruker, T., Prieschl-Strassmayr, E., Woisetschläger, M., The Th2 Cell Cytokines IL-4 and IL-13 regulate found in inflammatory zone 1/resistin-like molecule α gene expression by a STAT6 and CCAAT/enhancer-binding protein-dependent mechanism. J. Immunol., 170(4), 2003, 1789.
Loke, P., Nair, M.G., Parkinson, J., Guiliano, D., Blaxter, M., Allen, J.E., IL-4 dependent alternatively-activated macrophages have a distinctive in vivo gene expression phenotype. BMC Immunol, 3, 2002, 7.
Nair, M.G., Gallagher, I.J., Taylor, M.D., Loke, P., Coulson, P.S., Wilson, R.A., Maizels, R.M., Allen, J.E., Chitinase and Fizz family members are a generalized feature of nematode infection with selective upregulation of Ym1 and Fizz1 by antigen-presenting cells. Infect Immun 73:1 (2005), 385–394.
Raes, G., De Baetselier, P., Noël, W., Beschin, A., Brombacher, F., Hassanzadeh, G., Gh, Differential expression of FIZZ1 and Ym1 in alternatively versus classically activated macrophages. J Leukoc Biol 71:4 (2002), 597–602.
Jenkins, S.J., Ruckerl, D., Cook, P.C., Jones, L.H., Finkelman, F.D., van Rooijen, N., MacDonald, A.S., Allen, J.E., Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science 332:6035 (2011), 1284–1288.
Cook, P.C., Jones, L.H., Jenkins, S.J., Wynn, T.A., Allen, J.E., MacDonald, A.S., Alternatively activated dendritic cells regulate CD4+ T-cell polarization in vitro and in vivo. Proc Natl Acad Sci U S A 109:25 (2012), 9977–9982.
Loke, P., Gallagher, I., Nair, M.G., Zang, X., Brombacher, F., Mohrs, M., Allison, J.P., Allen, J.E., Alternative activation is an innate response to injury that requires CD4+ T cells to be sustained during chronic infection. J Immunol 179:6 (2007), 3926–3936.
Fang, C.L., Yin, L.J., Sharma, S., Kierstein, S., Wu, H.F., Eid, G., Haczku, A., Corrigan, C.J., Ying, S., Resistin-like molecule-β (RELM-β) targets airways fibroblasts to effect remodelling in asthma: from mouse to man. Clin Exp Allergy 45:5 (2015), 940–952.
Liu, T., Baek, H.A., Yu, H., Lee, H.J., Park, B.H., Ullenbruch, M., Liu, J., Nakashima, T., Choi, Y.Y., Wu, G.D., Chung, M.J., Phan, S.H., FIZZ2/RELM-β induction and role in pulmonary fibrosis. J Immunol 187:1 (2011), 450–461.
Mishra, A., Wang, M., Schlotman, J., Nikolaidis, N.M., DeBrosse, C.W., Karow, M.L., Rothenberg, M.E., Resistin-like molecule-β is an allergen-induced cytokine with inflammatory and remodeling activity in the murine lung. Am. J. Physiol. - Lung Cellular Mole. Physiol., 293(2), 2007, L305.
Grainge, C., Dulay, V., Ward, J., Sammut, D., Davies, E., Green, B., Lau, L., Cottey, L., Haitchi, H.-M., Davies, D.E., Howarth, P.H., Resistin-like molecule-β is induced following bronchoconstriction of asthmatic airways. Respirology 17:7 (2012), 1094–1100.
Barnes, S.L., Vidrich, A., Wang, M.L., Wu, G.D., Cominelli, F., Rivera-Nieves, J., Bamias, G., Cohn, S.M., Resistin-like molecule beta (RELM beta/FIZZ2) is highly expressed in the ileum of SAMP1/YitFc mice and is associated with initiation of ileitis. J. Immunol. 179:10 (2007), 7012–7020.
L.C. Osborne, K.L. Joyce, T. Alenghat, G.F. Sonnenberg, P.R. Giacomin, Y. Du, K.S. Bergstrom, B.A. Vallance, M.G. Nair, Resistin-like molecule (RELM) α promotes pathogenic Th17 cell responses and bacterial-induced intestinal inflammation, Journal of immunology (Baltimore, Md. : 1950) 190(5) (2013) 2292–2300.
Wang, M.L., Shin, M.E., Knight, P.A., Artis, D., Silberg, D.G., Suh, E., Wu, G.D., Regulation of RELM/FIZZ isoform expression by Cdx2 in response to innate and adaptive immune stimulation in the intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 288:5 (2005), G1074–G1083.
K. Chellappa, P. Deol, J.R. Evans, L.M. Vuong, G. Chen, N. Briançon, E. Bolotin, C. Lytle, M.G. Nair, F.M. Sladek, Opposing roles of nuclear receptor HNF4α isoforms in colitis and colitis-associated colon cancer, eLife 5 (2016) e10903.
Hayhurst, G.P., Lee, Y.-H., Lambert, G., Ward, J.M., Gonzalez, F.J., Hepatocyte nuclear factor 4α (Nuclear Receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol. Cell. Biol. 21:4 (2001), 1393–1403.
Kaestner, K.H., Making the liver what it is: the many targets of the transcriptional regulator HNF4α. Hepatology 51:2 (2010), 376–377.
Kim, K.H., Zhao, L., Moon, Y., Kang, C., Sul, H.S., Dominant inhibitory adipocyte-specific secretory factor (ADSF)/resistin enhances adipogenesis and improves insulin sensitivity. Proc Natl Acad Sci U S A 101:17 (2004), 6780–6785.
Shojima, N., Sakoda, H., Ogihara, T., Fujishiro, M., Katagiri, H., Anai, M., Onishi, Y., Ono, H., Inukai, K., Abe, M., Fukushima, Y., Kikuchi, M., Oka, Y., Asano, T., Humoral regulation of resistin expression in 3T3-L1 and mouse adipose cells. Diabetes, 51(6), 2002, 1737.
Nagaev, I., Andersen, M., Olesen, M.K., Nagaeva, O., Wikberg, J., Mincheva-Nilsson, L., Andersen, G.N., Resistin gene expression is downregulated in CD4+ T helper lymphocytes and CD14+ monocytes in rheumatoid arthritis responding to TNF-α Inhibition. Scand. J. Immunol. 84:4 (2016), 229–236.
Stan, D., Calin, M., Manduteanu, I., Pirvulescu, M., Gan, A.-M., Butoi, E.D., Simion, V., Simionescu, M., High glucose induces enhanced expression of resistin in human U937 monocyte-like cell line by MAPK- and NF-kB-dependent mechanisms; the modulating effect of insulin. Cell Tissue Res. 343:2 (2011), 379–387.
Seo, J.B., Noh, M.J., Yoo, E.J., Park, S.Y., Park, J., Lee, I.K., Park, S.D., Kim, J.B., Functional characterization of the human resistin promoter with adipocyte determination- and differentiation-dependent factor 1/sterol regulatory element binding protein 1c and CCAAT enhancer binding protein-α. Mol. Endocrinol. 17:8 (2003), 1522–1533.
Azuma, K., Oguchi, S., Matsubara, Y., Mamizuka, T., Murata, M., Kikuchi, H., Watanabe, K., Katsukawa, F., Yamazaki, H., Shimada, A., Saruta, T., Novel resistin promoter polymorphisms: association with serum resistin level in japanese obese individuals. Horm Metab Res 36:08 (2004), 564–570.
Azuma, K., Katsukawa, F., Oguchi, S., Murata, M., Yamazaki, H., Shimada, A., Saruta, T., Correlation between serum resistin level and adiposity in obese individuals. Obes. Res. 11:8 (2003), 997–1001.
Cho, Y.M., Ritchie, M.D., Moore, J.H., Park, J.Y., Lee, K.U., Shin, H.D., Lee, H.K., Park, K.S., Multifactor-dimensionality reduction shows a two-locus interaction associated with Type 2 diabetes mellitus. Diabetologia 47:3 (2004), 549–554.
Chung, S.S., Choi, H.H., Kim, K.W., Cho, Y.M., Lee, H.K., Park, K.S., Regulation of human resistin gene expression in cell systems: an important role of stimulatory protein 1 interaction with a common promoter polymorphic site. Diabetologia 48:6 (2005), 1150–1158.
Hu, W.-W., Tang, C.-H., Sun, Y., Lu, T.-T., Jiang, P., Wu, Y.-M., Wang, C.-Q., Yang, S.-F., Su, C.-M., Correlation between resistin gene polymorphism and clinical aspects of lung cancer. Medicine, 96(52), 2017.
Nair, M.G., Du, Y., Perrigoue, J.G., Zaph, C., Taylor, J.J., Goldschmidt, M., Swain, G.P., Yancopoulos, G.D., Valenzuela, D.M., Murphy, A., Karow, M., Stevens, S., Pearce, E.J., Artis, D., Alternatively activated macrophage-derived RELM-α is a negative regulator of type 2 inflammation in the lung. J. Exp. Med. 206:4 (2009), 937–952.
Su, Q., Zhou, Y., Johns, R.A., Bruton's tyrosine kinase (BTK) is a binding partner for hypoxia induced mitogenic factor (HIMF/FIZZ1) and mediates myeloid cell chemotaxis. FASEB J. 21:7 (2007), 1376–1382.
Fan, C., Su, Q., Li, Y., Liang, L., Angelini, D.J., Guggino, W.B., Johns, R.A., Hypoxia-induced mitogenic factor/FIZZ1 induces intracellular calcium release through the PLC-IP3 pathway. Am. J. Physiol. - Lung Cellular Mole. Physiol., 297(2), 2009, L263.
Yamaji-Kegan, K., Su, Q., Angelini, D.J., Champion, H.C., Johns, R.A., Hypoxia-induced mitogenic factor has proangiogenic and proinflammatory effects in the lung via VEGF and VEGF receptor-2. Am. J. Physiol. Lung Cell. Mol. Physiol. 291:6 (2006), L1159–L1168.
Liu, T., Hu, B., Choi, Y.Y., Chung, M., Ullenbruch, M., Yu, H., Lowe, J.B., Phan, S.H., Notch1 signaling in FIZZ1 induction of myofibroblast differentiation. Am. J. Pathol 174:5 (2009), 1745–1755.
Knipper, J.A., Willenborg, S., Brinckmann, J., Bloch, W., Maaß T., Wagener, R., Krieg, T., Sutherland, T., Munitz, A., Rothenberg, M.E., Niehoff, A., Richardson, R., Hammerschmidt, M., Allen, J.E., Eming, S.A., Interleukin-4 Receptor α signaling in myeloid cells controls collagen fibril assembly in skin repair. Immunity 43:4 (2015), 803–816.
Minutti, C.M., Jackson-Jones, L.H., García-Fojeda, B., Knipper, J.A., Sutherland, T.E., Logan, N., Ringqvist, E., Guillamat-Prats, R., Ferenbach, D.A., Artigas, A., Stamme, C., Chroneos, Z.C., Zaiss, D.M., Casals, C., Allen, J.E., Local amplifiers of IL-4Rα-mediated macrophage activation promote repair in lung and liver. Science 356:6342 (2017), 1076–1080.
Bosurgi, L., Cao, Y.G., Cabeza-Cabrerizo, M., Tucci, A., Hughes, L.D., Kong, Y., Weinstein, J.S., Licona-Limon, P., Schmid, E.T., Pelorosso, F., Gagliani, N., Craft, J.E., Flavell, R.A., Ghosh, S., Rothlin, C.V., Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells. Science 356:6342 (2017), 1072–1076.
Lee, M.-R., Lim, C.-J., Lee, Y.-H., Park, J.-G., Sonn, S.K., Lee, M.-N., Jung, I.-H., Jeong, S.-J., Jeon, S., Lee, M., Oh, K.S., Yang, Y., Kim, J.B., Choi, H.-S., Jeong, W., Jeong, T.-S., Yoon, W.K., Kim, H.C., Choi, J.-H., Oh, G.T., The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice. Nat. Commun., 5, 2014, 4410.
Wang, Y.-Q., Fan, C.-C., Chen, B.-P., Shi, J., Resistin-like molecule beta (RELM-β) Regulates proliferation of human diabetic nephropathy mesangial cells via mitogen-activated protein kinases (MAPK) signaling pathway. Med. Sci. Monitor : Internat. Med. J. Exp. Clin. Res. 23 (2017), 3897–3903.
Artis, D., Mei, L.W., Keilbaugh, S.A., He, W.M., Brenes, M., Swain, G.P., Knight, P.A., Donaldson, D.D., Lazar, M.A., Miller, H.R.P., Schad, G.A., Scott, P., Wu, G.D., RELM beta/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. PNAS 101:37 (2004), 13596–13600.
Herbert, D.R., Yang, J.Q., Hogan, S.P., Groschwitz, K., Khodoun, M., Munitz, A., Orekov, T., Perkins, C., Wang, Q., Brombacher, F., Urban, J.F., Rothenberg, M.E., Finkelman, F.D., Intestinal epithelial cell secretion of RELM-beta protects against gastrointestinal worm infection. J. Exp. Med. 206:13 (2009), 2947–2957.
Propheter, D.C., Chara, A.L., Harris, T.A., Ruhn, K.A., Hooper, L.V., Resistin-like molecule β is a bactericidal protein that promotes spatial segregation of the microbiota and the colonic epithelium. PNAS 114:42 (2017), 11027–11033.
Daquinag, A.C., Zhang, Y., Amaya-Manzanares, F., Simmons, P.J., Kolonin, M.G., An isoform of decorin is a resistin receptor on the surface of adipose progenitor cells. Cell Stem Cell 9:1 (2011), 74–86.
Tarkowski, A., Bjersing, J., Shestakov, A., Bokarewa, M.I., Resistin competes with lipopolysaccharide for binding to toll-like receptor 4. J. Cell Mol. Med. 14:6b (2010), 1419–1431.
Jang, J.C., Li, J., Gambini, L., Batugedara, H.M., Sati, S., Lazar, M.A., Fan, L., Pellecchia, M., Nair, M.G., Human resistin protects against endotoxic shock by blocking LPS–TLR4 interaction. Proc. Natl. Acad. Sci., 2017.
S. Jiang, D.W. Park, J.-M. Tadie, M. Gregoire, J. Deshane, J.F. Pittet, E. Abraham, J.W. Zmijewski, Human resistin promotes neutrophil pro-inflammatory activation, neutrophil extracellular trap formation, and increases severity of acute lung injury, Journal of immunology (Baltimore, Md. : 1950) 192(10) (2014) 4795–4803.
Singh, S., Chouhan, S., Mohammad, N., Bhat, M.K., Resistin causes G1 arrest in colon cancer cells through upregulation of SOCS3. Febs Lett. 591:10 (2017), 1371–1382.
Kim, S., Kim, S.Y., Pribis, J.P., Lotze, M., Mollen, K.P., Shapiro, R., Loughran, P., Scott, M.J., Billiar, T.R., Signaling of high mobility group box 1 (HMGB1) through toll-like receptor 4 in macrophages requires CD14. Mol Med 19 (2013), 88–98.
Trompette, A., Divanovic, S., Visintin, A., Blanchard, C., Hegde, R.S., Madan, R., Thorne, P.S., Wills-Karp, M., Gioannini, T.L., Weiss, J.P., Karp, C.L., Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. Nature 457:7229 (2009), 585–588.
Wang, Y., Qian, Y., Fang, Q., Zhong, P., Li, W., Wang, L., Fu, W., Zhang, Y., Xu, Z., Li, X., Liang, G., Saturated palmitic acid induces myocardial inflammatory injuries through direct binding to TLR4 accessory protein MD2. Nat. Commun., 8, 2017, 13997.
Goodridge, H.S., Marshall, F.A., Else, K.J., Houston, K.M., Egan, C., Al-Riyami, L., Liew, F.Y., Harnett, W., Harnett, M.M., Immunomodulation via novel use of TLR4 by the filarial nematode phosphorylcholine-containing secreted product, ES-62. J Immunol 174:1 (2005), 284–293.
Martin, I., Cabán-Hernández, K., Figueroa-Santiago, O., Espino, A.M., Fasciola hepatica fatty acid binding protein inhibits TLR4 activation and suppresses the inflammatory cytokines induced by lipopolysaccharide in vitro and in vivo. J Immunol 194:8 (2015), 3924–3936.
Yu, L., Wang, L., Chen, S., Endogenous toll-like receptor ligands and their biological significance. J. Cell. Mol. Med. 14:11 (2010), 2592–2603.
Lee, S., Lee, H.-C., Kwon, Y.-W., Lee, S.E., Cho, Y., Kim, J., Lee, S., Kim, J.-Y., Lee, J., Yang, H.-M., Mook-Jung, I., Nam, K.-Y., Chung, J., Lazar, M.A., Kim, H.-S., Adenylyl cyclase-associated protein 1(CAP1) is a receptor for human resistin and mediates inflammatory actions of human monocytes. Cell metabolism 19:3 (2014), 484–497.
Suragani, M., Aadinarayana, V.D., Pinjari, A.B., Tanneeru, K., Guruprasad, L., Banerjee, S., Pandey, S., Chaudhuri, T.K., Ehtesham, N.Z., Human resistin, a proinflammatory cytokine, shows chaperone-like activity. Proc Natl Acad Sci U S A 110:51 (2013), 20467–20472.
Chen, G., Chan, A.J., Chung, J.I., Jang, J.C., Osborne, L.C., Nair, M.G., Polarizing the T helper 17 response in Citrobacter rodentium infection via expression of resistin-like molecule α. Gut Microbes 5:3 (2014), 363–368.
Nair, M.G., Guild, K.J., Du, Y., Zaph, C., Yancopoulos, G.D., Valenzuela, D.M., Murphy, A., Stevens, S., Karow, M., Artis, D., Goblet cell-derived resistin-like molecule beta augments CD4+ T cell production of IFN-gamma and infection-induced intestinal inflammation. J Immunol 181:7 (2008), 4709–4715.
Bergstrom, K.S.B., Morampudi, V., Chan, J.M., Bhinder, G., Lau, J., Yang, H., Ma, C., Huang, T., Ryz, N., Sham, H.P., Zarepour, M., Zaph, C., Artis, D., Nair, M., Vallance, B.A., Goblet Cell Derived RELM-beta Recruits CD4(+) T Cells during Infectious Colitis to Promote Protective Intestinal Epithelial Cell Proliferation. Plos Pathogens, 11(8), 2015.
Meng, Z.J., Zhang, Y.H., Wei, Z.Q., Liu, P., Kang, J., Ma, D.Q., Ke, C.Z., Chen, Y., Luo, J., Gong, Z.J., High serum resistin associates with intrahepatic inflammation and necrosis: an index of disease severity for patients with chronic HBV infection. Bmc Gastroenterology, 17, 2017, 9.
Tiftikci, A., Atug, O., Yilmaz, Y., Eren, F., Ozdemir, F.T., Yapali, S., Ozdogan, O., Celikel, C.A., Imeryuz, N., Tozun, N., Serum levels of adipokines in patients with chronic HCV Infection: relationship with steatosis and fibrosis. Arch. Med. Res. 40:4 (2009), 294–298.
Bertolani, C., Sancho-Bru, P., Failli, P., Bataller, R., Aleffi, S., DeFranco, R., Mazzinghi, B., Romagnani, P., Milani, S., Ginés, P., Colmenero, J., Parola, M., Gelmini, S., Tarquini, R., Laffi, G., Pinzani, M., Marra, F., Resistin as an intrahepatic cytokine : overexpression during chronic injury and induction of proinflammatory actions in hepatic stellate cells. Am. J. Pathology 169:6 (2006), 2042–2053.
Doherty, T.A., Khorram, N., Sugimoto, K., Sheppard, D., Rosenthal, P., Cho, J.Y., Pham, A., Miller, M., Croft, M., Broide, D.H., Alternaria induces STAT6-dependent acute airway eosinophilia and epithelial FIZZ1 expression that promotes airway fibrosis and epithelial thickness. J Immunol 188:6 (2012), 2622–2629.
Yamaji-Kegan, K., Takimoto, E., Zhang, A., Weiner, N.C., Meuchel, L.W., Berger, A.E., Cheadle, C., Johns, R.A., Hypoxia-induced mitogenic factor (FIZZ1/RELMα) induces endothelial cell apoptosis and subsequent interleukin-4-dependent pulmonary hypertension. Am. J. Physiol. Lung. Cell Mol. Physiol. 306:12 (2014), L1090–L1103.
Munitz, A., Cole, E.T., Karo-Atar, D., Finkelman, F.D., Rothenberg, M.E., Resistin-like molecule-α regulates IL-13-induced chemokine production but not allergen-induced airway responses. Am. J. Respir. Cell. Mol. Biol. 46:5 (2012), 703–713.
A. Munitz, A. Waddell, L. Seidu, E.T. Cole, R. Ahrens, S.P. Hogan, M.E. Rothenberg, Resistin-like molecule alpha enhances myeloid cell activation and promotes colitis, J Allergy Clin Immunol 122(6) (2008) 1200–1207.e1.
Hogan, S.P., Seidu, L., Blanchard, C., Groschwitz, K., Mishra, A., Karow, M.L., Ahrens, R., Artis, D., Murphy, A.J., Valenzuela, D.M., Yancopoulos, G.D., Rothenberg, M.E., Resistin-like molecule beta regulates innate colonic function: barrier integrity and inflammation susceptibility. J. Allergy Clin. Immunol. 118:1 (2006), 257–268.
Gieseck, R.L., Wilson, M.S., Wynn, T.A., Type 2 immunity in tissue repair and fibrosis. Nat. Rev. Immunol. 18:1 (2018), 62–76.
Martins, V., De Los Santos, F.G., Wu, Z., Capetozzi, V., Phan, S.H., Liu, T.J., FIZZ1-Induced myofibroblast transdifferentiation from adipocytes and its potential rote in dermal fibrosis and lipoatrophy. Am. J. Pathol. 185:10 (2015), 2768–2776.
Liu, T., Yu, H., Ullenbruch, M., Jin, H., Ito, T., Wu, Z., Liu, J., Phan, S.H., The in vivo fibrotic role of FIZZ1 in pulmonary fibrosis. PLoS One, 9(2), 2014, e88362.
Yamaji-Kegan, K., Su, Q., Angelini, D.J., Myers, A.C., Cheadle, C., Johns, R.A., Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMalpha) increases lung inflammation and activates pulmonary microvascular endothelial cells via an IL-4-dependent mechanism. J Immunol 185:9 (2010), 5539–5548.
Liu, T.J., Baek, H.A., Yu, H.F., Lee, H.J., Park, B.H., Ullenbruch, M., Liu, J.H., Nakashima, T., Choi, Y.Y., Wu, G.D., Chung, M.J., Phan, S.H., FIZZ2/RELM-beta Induction and Role in Pulmonary Fibrosis. J. Immunol. 187:1 (2011), 450–461.
Schwartz, D.R., Lazar, M.A., Human resistin: found in translation from mouse to man. Trends Endocrinol. Metab. 22:7 (2011), 259–265.
Montoya, J.G., Holmes, T.H., Anderson, J.N., Maecker, H.T., Rosenberg-Hasson, Y., Valencia, I.J., Chu, L., Younger, J.W., Tato, C.M., Davis, M.M., Cytokine signature associated with disease severity in chronic fatigue syndrome patients. Proc. Natl. Acad. Sci. USA 114:34 (2017), E7150–E7158.
Zheng, L.D., Weng, M.X., He, J., Yang, X.P., Jiang, G.S., Tong, Q.S., Expression of resistin-like molecule beta in gastric cancer: its relationship with clinicopathological parameters and prognosis. Virchows Arch. 456:1 (2010), 53–63.
Asterholm, I.W., Kim-Muller, J.Y., Rutkowski, J.M., Crewe, C., Tao, C., Scherer, P.E., Pathological Type-2 immune response, enhanced tumor growth, and glucose intolerance in Retn/beta (RELM beta) null mice a model of intestinal immune system dysfunction in disease susceptibility. Am. J. Pathol. 186:9 (2016), 2404–2416.
Jiang, R., Zhao, C.M., Wang, X.Y., Wang, S.X., Sun, X.G., Tian, Y., Song, W., Resistin-like molecule-beta promotes invasion and migration of gastric carcinoma cells. Med. Sci. Monit. 22 (2016), 937–942.
Pang, J.A., Shi, Q.F., Liu, Z.Q., He, J., Liu, H.A., Lin, P., Cui, J.W., Yang, J., Resistin induces multidrug resistance in myeloma by inhibiting cell death and upregulating ABC transporter expression. Haematologica 102:7 (2017), 1273–1280.
Kumamoto, Y., Camporez, J.P.G., Jurczak, M.J., Shanabrough, M., Horvath, T., Shulman, G.I., Iwasaki, A., CD301b(+) mononuclear phagocytes maintain positive energy balance through secretion of resistin-like molecule alpha. Immunity 45:3 (2016), 583–596.
Munitz, A., Seidu, L., Cole, E.T., Ahrens, R., Hogan, S.P., Rothenberg, M.E., Resistin-like molecule a decreases glucose tolerance during intestinal inflammation. J. Immunol. 182:4 (2009), 2357–2363.
Odegaard, J.I., Chawla, A., Type 2 responses at the interface between immunity and fat metabolism. Curr Opin Immunol 36 (2015), 67–72.
Shu, C.J., Benoist, C., Mathis, D., The immune system's involvement in obesity-driven type 2 diabetes. Semin Immunol 24:6 (2012), 436–442.
M.A. Hildebrandt, C. Hoffman, S.A. Sherrill-Mix, S.A. Keilbaugh, M. Hamady, Y.-Y. Chen, R. Knight, R.S. Ahima, F. Bushman, G.D. Wu, High Fat Diet Determines the Composition of the Murine Gut Microbiome Independently of Obesity, Gastroenterology 137(5) (2009) 1716-24.e1-2.
A. Kushiyama, T. Shojima N Fau - Ogihara, K. Ogihara T Fau - Inukai, H. Inukai K Fau - Sakoda, M. Sakoda H Fau - Fujishiro, Y. Fujishiro M Fau - Fukushima, M. Fukushima Y Fau - Anai, H. Anai M Fau - Ono, N. Ono H Fau - Horike, A.Y.I. Horike N Fau - Viana, Y. Viana Ay Fau - Uchijima, K. Uchijima Y Fau - Nishiyama, T. Nishiyama K Fau - Shimosawa, T. Shimosawa T Fau - Fujita, H. Fujita T Fau - Katagiri, Y. Katagiri H Fau - Oka, H. Oka Y Fau - Kurihara, T. Kurihara H Fau - Asano, T. Asano, Resistin-like molecule beta activates MAPKs, suppresses insulin signaling in hepatocytes, and induces diabetes, hyperlipidemia, and fatty liver in transgenic mice on a high fat diet, Journal of Biological Chemistry (0021-9258 (Print)) (2005).
Al Hannan, F., Culligan, K.G., Human resistin and the RELM of Inflammation in diabesity. Diabetol Metab Syndr, 7, 2015, 54.
Smekal, A., Vaclavik, J., Adipokines and cardiovascular disease: a comprehensive review. Biomedical papers 161:1 (2017), 31–40.
Qatanani, M., Szwergold, N.R., Greaves, D.R., Ahima, R.S., Lazar, M.A., Macrophage-derived human resistin exacerbates adipose tissue inflammation and insulin resistance in mice. J Clin Invest 119:3 (2009), 531–539.
Nagaev, I., Smith, U., Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle. Biochem. Biophys. Res. Commun. 285:2 (2001), 561–564.
Hivert, M.F., Manning, A.K., McAteer, J.B., Dupuis, J., Fox, C.S., Cupples, L.A., Meigs, J.B., Florez, J.C., Association of variants in RETN with plasma resistin levels and diabetes-related traits in the Framingham Offspring Study. Diabetes 58:3 (2009), 750–756.
Heilbronn, L.K., Rood, J., Janderova, L., Albu, J.B., Kelley, D.E., Ravussin, E., Smith, S.R., Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects. J. Clin. Endocrinol. Metab. 89:4 (2004), 1844–1848.
Graveleau, C., Zaha, V.G., Mohajer, A., Banerjee, R.R., Dudley-Rucker, N., Steppan, C.M., Rajala, M.W., Scherer, P.E., Ahima, R.S., Lazar, M.A., Abel, E.D., Mouse and human resistins impair glucose transport in primary mouse cardiomyocytes, and oligomerization is required for this biological action. J. Biol. Chem. 280:36 (2005), 31679–31685.
Wang, J.H., Lee, C.J., Yang, C.F., Chen, Y.C., Hsu, B.G., Serum resistin as an independent marker of aortic stiffness in patients with coronary artery disease. Plos One, 12(8), 2017.
