All Title Author
Keywords Abstract


IL-21 Modulates Release of Proinflammatory Cytokines in LPS-Stimulated Macrophages through Distinct Signaling Pathways

DOI: 10.1155/2013/548073

Full-Text   Cite this paper   Add to My Lib

Abstract:

The aim of this study was to investigate the anti-inflammatory effect of IL-21 on LPS-induced mouse peritoneal macrophages. The results showed that IL-21 significantly inhibited LPS-induced mRNA expression of IL-1β, TNF-α, and IL-6 in macrophages, but not of IFN-γ, IL-10, CCL5, or CXCL2. ELISA analysis showed that IL-21 also suppressed LPS-induced production of TNF-α and IL-6 in culture supernatants. Western blot analysis showed that IL-21 clearly inhibited ERK and IκBα phosphorylation and NF-κB translocation in LPS-stimulated macrophages, but it increased STAT3 phosphorylation. Flow cytometric and Western blot analysis showed that IL-21 decreased M1 macrophages surface markers expression of CD86, iNOS, and TLR4 in LPS-stimulated cells. All results suggested that IL-21 decreases IL-6 and TNF-α production via inhibiting the phosphorylation of ERK and translocation of NF-κB and promotes a shift from the M1 to M2 macrophage phenotype by decreasing the expression of CD86, iNOS, and TLR4 and by increasing STAT3 phosphorylation in LPS-stimulated cells. 1. Introduction Interleukin-21 (IL-21) is produced by activated CD4+ T-cells, natural killer T cells (NKT cells), and follicular T helper cells. The IL-21 receptor was discovered in 2000 as an orphan receptor, first denoted as NILR for novel interleukin receptor and now as IL-21R [1, 2]. IL-21 receptor expression has been detected on CD4+ T cells, CD8+ T cells, B cells, NK cells, macrophages, and dendritic cells (DCs) [1–6], suggesting that IL-21 has a broad range of functions. In addition, the IL-21 receptor is a member of a family of receptors that share the γ chain (γc). Analogous to the other γc family cytokines, IL-21 activates both Jak1 and Jak3 [1, 7, 8], and weakly activates Stat5 proteins [9]. Stat3 appears to be the most important STAT protein for IL-21 signaling. In addition, the phosphoinositol 3-kinase/Akt (PI3K/Akt) and Ras/MAP kinase (MAPK) pathways also contribute to IL-21 signaling [10]. IL-21 also clearly has an important effect on B cells, T cells, and NK T cells. For example, IL-21 can augment anti-CD40-induced human B-cell proliferation, but it inhibits proliferation to anti-IgM and IL-4 [2] and can increase the proliferation of NK T cells in response to in vitro stimulation with anti-CD3, but only when combined with either IL-2 or IL-15 [11]. Macrophages are important innate immune cells that are strategically located throughout the body tissues, where they ingest and process foreign materials, dead cells, and debris and recruit additional macrophages in response to inflammatory signals.

References

[1]  K. Ozaki, K. Kikly, D. Michalovich, P. R. Young, and W. J. Leonard, “Cloning of a type I cytokine receptor most related to the IL-2 receptor β chain,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 21, pp. 11439–11444, 2000.
[2]  J. Parrish-Novak, S. R. Dillon, A. Nelson et al., “Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function,” Nature, vol. 408, no. 6808, pp. 57–63, 2000.
[3]  H. Jin, R. Carrio, A. Yu, and T. R. Malek, “Distinct activation signals determine whether IL-21 induces B cell costimulation, growth arrest, or Bim-dependent apoptosis,” The Journal of Immunology, vol. 173, no. 1, pp. 657–665, 2004.
[4]  K. Brandt, S. Bulfone-Paus, D. C. Foster, and R. Rückert, “Interleukin-21 inhibits dendritic cell activation and maturation,” Blood, vol. 102, no. 12, pp. 4090–4098, 2003.
[5]  J. H. W. Distler, A. Jüngel, O. Kowal-Bielecka et al., “Expression of interleukin-21 receptor in epidermis from patients with systemic sclerosis,” Arthritis & Rheumatism, vol. 52, no. 3, pp. 856–864, 2005.
[6]  R. Caruso, D. Fina, I. Peluso et al., “IL-21 is highly produced in Helicobacter pylori-infected gastric mucosa and promotes gelatinases synthesis,” The Journal of Immunology, vol. 178, no. 9, pp. 5957–5965, 2007.
[7]  H. Asao, C. Okuyama, S. Kumaki et al., “Cutting edge: the common γ-chain is an indispensable subunit of the IL-21 receptor complex,” The Journal of Immunology, vol. 167, no. 1, pp. 1–5, 2001.
[8]  T. Habib, S. Senadheera, K. Weinberg, and K. Kaushansky, “The common γ chain (γc) is a required signaling component of the IL-21 receptor and supports IL-21-induced cell proliferation via JAK3,” Biochemistry, vol. 41, no. 27, pp. 8725–8731, 2002.
[9]  R. Spolski and W. J. Leonard, “Interleukin-21: basic biology and implications for cancer and autoimmunity,” Annual Review of Immunology, vol. 26, pp. 57–79, 2008.
[10]  R. Zeng, R. Spolski, E. Casas, W. Zhu, D. E. Levy, and W. J. Leonard, “The molecular basis of IL-21-mediated proliferation,” Blood, vol. 109, no. 10, pp. 4135–4142, 2007.
[11]  J. M. Coquet, K. Kyparissoudis, D. G. Pellicci et al., “IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production,” The Journal of Immunology, vol. 178, no. 5, pp. 2827–2834, 2007.
[12]  T. Lawrence and G. Natoli, “Transcriptional regulation of macrophage polarization: enabling diversity with identity,” Nature Reviews Immunology, vol. 11, no. 11, pp. 750–761, 2011.
[13]  P. J. Murray and T. A. Wynn, “Obstacles and opportunities for understanding macrophage polarization,” The Journal of Leukocyte Biology, vol. 89, no. 4, pp. 557–563, 2011.
[14]  D. M. Mosser and J. P. Edwards, “Exploring the full spectrum of macrophage activation,” Nature Reviews Immunology, vol. 8, no. 12, pp. 958–969, 2008.
[15]  G. Liu and E. Abraham, “MicroRNAs in immune response and macrophage polarization,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 33, no. 2, pp. 170–177, 2013.
[16]  T. D. Gilmore, “Introduction to NF-κB: players, pathways, perspectives,” Oncogene, vol. 25, no. 51, pp. 6680–6684, 2006.
[17]  A. R. Brasier, “The NF-κB regulatory network,” Cardiovascular Toxicology, vol. 6, no. 2, pp. 111–130, 2006.
[18]  N. D. Perkins, “Integrating cell-signalling pathways with NF-κB and IKK function,” Nature Reviews Molecular Cell Biology, vol. 8, no. 1, pp. 49–62, 2007.
[19]  N. Akamatsu, Y. Yamada, H. Hasegawa et al., “High IL-21 receptor expression and apoptosis induction by IL-21 in follicular lymphoma,” Cancer Letters, vol. 256, no. 2, pp. 196–206, 2007.
[20]  C. Bogdan, M. R?llinghoff, and A. Diefenbach, “The role of nitric oxide in innate immunity,” Immunological Reviews, vol. 173, pp. 17–26, 2000.
[21]  A. Sica and A. Mantovani, “Macrophage plasticity and polarization: in vivo veritas,” The Journal of Clinical Investigation, vol. 122, no. 3, pp. 787–795, 2012.
[22]  S.-H. Li, V. S. Hawthorne, C. L. Neal et al., “Upregulation of neutrophil gelatinase-associated lipocalin by ErbB2 through nuclear factor-κB activation,” Cancer Research, vol. 69, no. 24, pp. 9163–9168, 2009.
[23]  R. Rückert, S. Bulfone-Paus, and K. Brandt, “Interleukin-21 stimulates antigen uptake, protease activity, survival and induction of CD4+ T cell proliferation by murine macrophages,” Clinical & Experimental Immunology, vol. 151, no. 3, pp. 487–495, 2008.
[24]  Y. Liu, B. Yang, J. Ma et al., “Interleukin-21 induces the differentiation of human Tc22 cells via phosphorylation of signal transducers and activators of transcription,” Immunology, vol. 132, no. 4, pp. 540–548, 2011.
[25]  M. R. Guimar?es, F. R. Leite, L. C. Spolidorio, K. L. Kirkwood, and C. Rossa Jr., “Curcumin abrogates LPS-induced pro-inflammatory cytokines in RAW 264.7 macrophages. Evidence for novel mechanisms involving SOCS-1, -3 and p38 MAPK,” Archives of Oral Biology, vol. 58, no. 10, pp. 1309–1307, 2013.
[26]  M. Strengell, A. Lehtonen, S. Matikainen, and I. Julkunen, “IL-21 enhances SOCS gene expression and inhibits LPS-induced cytokine production in human monocyte-derived dendritic cells,” The Journal of Leukocyte Biology, vol. 79, no. 6, pp. 1279–1285, 2006.
[27]  T. Bergsbaken, S. L. Fink, and B. T. Cookson, “Pyroptosis: host cell death and inflammation,” Nature Reviews Microbiology, vol. 7, no. 2, pp. 99–109, 2009.
[28]  J. Mo and J. A. Duncan, “Assessing ATP binding and hydrolysis by NLR proteins,” Methods in Molecular Biology, vol. 1040, no. 1, pp. 153–168, 2013.
[29]  M. K. McCoy, K. A. Ruhn, A. Blesch, and M. G. Tansey, “TNF: a key neuroinflammatory mediator of neurotoxicity and neurodegeneration in models of Parkinson's disease,” Advances in Experimental Medicine and Biology, vol. 691, pp. 539–540, 2011.
[30]  J.-N. Dai, Y. Zong, L.-M. Zhong et al., “Gastrodin inhibits expression of inducible NO synthase, cyclooxygenase-2 and proinflammatory cytokines in cultured LPS-stimulated microglia via MAPK pathways,” PLoS ONE, vol. 6, no. 7, Article ID e21891, 2011.
[31]  Y. H. Choi, G. Y. Jin, G. Z. Li, and G. H. Yan, “Cornuside suppresses lipopolysaccharide-induced inflammatory mediators by inhibiting nuclear factor-κ B activation in RAW 264.7 macrophages,” Biological & Pharmaceutical Bulletin, vol. 34, no. 7, pp. 959–966, 2011.
[32]  A. Majdalawieh and H.-S. Ro, “Regulation of IκBα function and NF-κB signaling: AEBP1 is a novel proinflammatory mediator in macrophages,” Mediators of Inflammation, vol. 2010, Article ID 823821, 27 pages, 2010.
[33]  S. L. Foster, D. C. Hargreaves, and R. Medzhitov, “Gene-specific control of inflammation by TLR-induced chromatin modifications,” Nature, vol. 447, no. 7147, pp. 972–978, 2007.
[34]  P. J. Murray and T. A. Wynn, “Protective and pathogenic functions of macrophage subsets,” Nature Reviews Immunology, vol. 11, no. 11, pp. 723–737, 2011.
[35]  S. K. Biswas and E. Lopez-Collazo, “Endotoxin tolerance: new mechanisms, molecules and clinical significance,” Trends in Immunology, vol. 30, no. 10, pp. 475–487, 2009.

Full-Text

comments powered by Disqus