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Gene Review

Cxcl2  -  chemokine (C-X-C motif) ligand 2

Mus musculus

Synonyms: C-X-C motif chemokine 2, CINC-2a, GROb, Gro2, MIP-2, ...
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Disease relevance of Cxcl2

  • We propose that this KC/MIP-2 chemokine cascade may contribute to the persistence of mononuclear cell infiltration in demyelinating autoimmune diseases [1].
  • Intratracheal Escherichia coli endotoxin provoked elevated lavage TNF-alpha, IL-6, and MIP-2 levels, peaking after 6 h in parallel with increased alveolar neutrophil numbers, in the absence of vascular leakage [2].
  • Increased MIP-2 was correlated with severity of sepsis (P < 0.001) [3].
  • MIP-2 contributes to the inflammatory response and overall mortality in this model of severe septic peritonitis, possibly by increasing recruitment of neutrophils, which clear bacteria but may also injure the host [3].
  • Moreover, in vivo intramyocardial injection of either an adenovirus expressing MIP-2 or the recombinant protein itself was sufficient to upregulate JE/MCP-1 production even in the absence of ischemia [4].

High impact information on Cxcl2

  • Compound deletion of ctxAB, hlyA, hapA, and rtxA created strain KFV101, which colonized the lung but induced pulmonary disease with limited inflammation and significantly reduced serum titers of IL-6 and MIP-2 [5].
  • These results document selective insensitivity of myeloid progenitor cells from mIL-8Rh(-/-) mice to inhibition by huIL-8 and mouse MIP-2 and a large expansion of myeloid progenitors in these mice, the latter effect being environmentally inducible [6].
  • Thus, biglycan, upon release from the ECM or from macrophages, can boost inflammation by signaling through TLR4 and TLR2, thereby enhancing the synthesis of TNF-alpha and MIP-2 [7].
  • These findings were associated with a reduction in eotaxin mRNA and an increase in mRNA for the T-cell chemokines macrophage inflammatory protein-2 (MIP-2), MIP-1beta, and RANTES [8].
  • However, the levels of TNFalpha and MIP-2 and neutrophilia were significantly higher in the lung of IL-6-/- mice [9].

Chemical compound and disease context of Cxcl2


Biological context of Cxcl2


Anatomical context of Cxcl2


Associations of Cxcl2 with chemical compounds

  • Treatment of BMM with trichostatin A (TSA), an inhibitor of HDACs, enhanced LPS-induced expression of the Cox-2, Cxcl2, and Ifit2 genes [21].
  • The peritoneal levels of TNF-alpha, MIP-2, KC, and MCP-1 were similarly elevated in LysMcre/Stat3flox/- mice rendered leukopenic by cyclophosphamide treatment as compared with the controls [22].
  • Organ damage was significantly reduced by inosine treatment, which was associated at the tissue level with an increased hepatic NAD+/NADH ratio, decreased MPO activity in the lung, reduced MDA formation in the gut and liver, and decreased MIP-1alpha and MIP-2 in the lung and liver [23].
  • The hypothesis that the neutrophil chemoattractant CXC chemokines KC and macrophage inflammatory protein-2 (MIP-2) are involved in neutrophil transmigration and liver injury was tested in C3Heb/FeJ mice treated with galactosamine (Gal, 700 mg/kg), endotoxin (ET, 100 microg/kg), or Gal + ET (Gal/ET) [24].
  • Conversely, ovariectomy, which abrogated basal 17 beta-estradiol levels and increased the severity of EAE, enhanced the expression of MIP-1 alpha and MIP-2 that were over-expressed by inflammatory mononuclear cells in SC [25].

Physical interactions of Cxcl2

  • This induction was abolished by a mutation targeted to an NF-kappaB binding site in the MIP-2 promoter [26].

Enzymatic interactions of Cxcl2


Regulatory relationships of Cxcl2

  • A specific PPARgamma antagonist (GW9662) had no effect on the inhibitory action of 15d-PGJ(2) and PGA1 in LPS-induced chemokine mRNA expression and on the synergistic action of 15d-PGJ(2) in LPS-induced MIP-2 (CXCL2) expression [14].
  • In addition, low levels of MIP-1alpha and MIP-1beta were induced following treatment with MIP-2 or KC [1].
  • Previously published results obtained in ob/ob mice were similar except for O(3)-induced neutrophils and MIP-2, which were not different from WT mice [27].
  • Inclusion of IL-10 neutralizing antibody in the culture medium significantly (p<0.05) enhanced TNF-alpha-induced IL-6 and MIP-2 production by both corneal cell types [28].
  • This study examined the effect of Linomide on the production of CXC chemokines, including macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC) and interleukin-10 (IL-10) in lipopolysaccharide (LPS)/d-galactosamine (Gal)-induced liver injury in mice [29].

Other interactions of Cxcl2

  • CIA mice passively immunized with antibodies directed against either MIP-1 alpha or MIP-2 demonstrated a delay in the onset of arthritis and a reduction of the severity of arthritis [30].
  • These data suggest that MIP-1 alpha and MIP-2 play a crucial role in the initiation and maintenance, while IL-10 appears to play a regulatory role during the development of experimental arthritis [30].
  • Two different strains of mice efficiently cleared aerosolized H. influenzae concurrent with a brisk elaboration of IL-1beta, IL-6, TNF-alpha, macrophage-inflammatory protein (MIP)-1alpha, and MIP-2 in bronchoalveolar lavage and a corresponding mobilization of intrapulmonary neutrophils [31].
  • The mesangial cell receptor for MIP-2 and/or KC is unknown but is not CXC-chemokine receptor-2 [32].
  • No effect on MIP-2 and MCP-1 levels was observed [33].

Analytical, diagnostic and therapeutic context of Cxcl2


  1. Macrophage inflammatory protein-2 and KC induce chemokine production by mouse astrocytes. Luo, Y., Fischer, F.R., Hancock, W.W., Dorf, M.E. J. Immunol. (2000) [Pubmed]
  2. Alveolar JE/MCP-1 and endotoxin synergize to provoke lung cytokine upregulation, sequential neutrophil and monocyte influx, and vascular leakage in mice. Maus, U., Huwe, J., Maus, R., Seeger, W., Lohmeyer, J. Am. J. Respir. Crit. Care Med. (2001) [Pubmed]
  3. Elevated levels of macrophage inflammatory protein 2 in severe murine peritonitis increase neutrophil recruitment and mortality. Walley, K.R., Lukacs, N.W., Standiford, T.J., Strieter, R.M., Kunkel, S.L. Infect. Immun. (1997) [Pubmed]
  4. Chemokine expression in myocardial ischemia: MIP-2 dependent MCP-1 expression protects cardiomyocytes from cell death. Tarzami, S.T., Cheng, R., Miao, W., Kitsis, R.N., Berman, J.W. J. Mol. Cell. Cardiol. (2002) [Pubmed]
  5. The contribution of accessory toxins of Vibrio cholerae O1 El Tor to the proinflammatory response in a murine pulmonary cholera model. Fullner, K.J., Boucher, J.C., Hanes, M.A., Haines, G.K., Meehan, B.M., Walchle, C., Sansonetti, P.J., Mekalanos, J.J. J. Exp. Med. (2002) [Pubmed]
  6. Involvement of Interleukin (IL) 8 receptor in negative regulation of myeloid progenitor cells in vivo: evidence from mice lacking the murine IL-8 receptor homologue. Broxmeyer, H.E., Cooper, S., Cacalano, G., Hague, N.L., Bailish, E., Moore, M.W. J. Exp. Med. (1996) [Pubmed]
  7. The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. Schaefer, L., Babelova, A., Kiss, E., Hausser, H.J., Baliova, M., Krzyzankova, M., Marsche, G., Young, M.F., Mihalik, D., Götte, M., Malle, E., Schaefer, R.M., Gröne, H.J. J. Clin. Invest. (2005) [Pubmed]
  8. Roles of TH1 and TH2 cytokines in a murine model of allergic dermatitis. Spergel, J.M., Mizoguchi, E., Oettgen, H., Bhan, A.K., Geha, R.S. J. Clin. Invest. (1999) [Pubmed]
  9. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. Xing, Z., Gauldie, J., Cox, G., Baumann, H., Jordana, M., Lei, X.F., Achong, M.K. J. Clin. Invest. (1998) [Pubmed]
  10. Involvement of the neuropeptide substance P in lung inflammation induced by hepatic ischemia/reperfusion. Okaya, T., Holthaus, R., Kato, A., Lentsch, A.B. Inflamm. Res. (2004) [Pubmed]
  11. Poly(ADP-ribose) polymerase is a regulator of chemokine production: relevance for the pathogenesis of shock and inflammation. Haskó, G., Mabley, J.G., Németh, Z.H., Pacher, P., Deitch, E.A., Szabó, C. Mol. Med. (2002) [Pubmed]
  12. Impairment of endotoxin-induced macrophage inflammatory protein 2 gene expression in alveolar macrophages in streptozotocin-induced diabetes in mice. Amano, H., Yamamoto, H., Senba, M., Oishi, K., Suzuki, S., Fukushima, K., Mukaida, N., Matsushima, K., Eguchi, K., Nagatake, T. Infect. Immun. (2000) [Pubmed]
  13. Administration of isoferulic acid improved the survival rate of lethal influenza virus pneumonia in mice. Sakai, S., Ochiai, H., Mantani, N., Kogure, T., Shibahara, N., Terasawa, K. Mediators of inflammation. (2001) [Pubmed]
  14. Upregulation of MIP-2 (CXCL2) expression by 15-deoxy-Delta(12,14)-prostaglandin J(2) in mouse peritoneal macrophages. Kim, H.Y., Kim, H.S. Immunol. Cell Biol. (2007) [Pubmed]
  15. Role of chemokines and formyl peptides in pneumococcal pneumonia-induced monocyte/macrophage recruitment. Fillion, I., Ouellet, N., Simard, M., Bergeron, Y., Sato, S., Bergeron, M.G. J. Immunol. (2001) [Pubmed]
  16. Macrophage inflammatory protein 2 inhibits beta-amyloid peptide (1-42)-mediated hippocampal neuronal apoptosis through activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways. Watson, K., Fan, G.H. Mol. Pharmacol. (2005) [Pubmed]
  17. Oxygen radical-dependent expression of CXC chemokines regulate ischemia/reperfusion-induced leukocyte adhesion in the mouse colon. Riaz, A.A., Schramm, R., Sato, T., Menger, M.D., Jeppsson, B., Thorlacius, H. Free Radic. Biol. Med. (2003) [Pubmed]
  18. Inhibition of SAPK2a/p38 prevents hnRNP A0 phosphorylation by MAPKAP-K2 and its interaction with cytokine mRNAs. Rousseau, S., Morrice, N., Peggie, M., Campbell, D.G., Gaestel, M., Cohen, P. EMBO J. (2002) [Pubmed]
  19. Fas signal links innate and adaptive immunity by promoting dendritic-cell secretion of CC and CXC chemokines. Guo, Z., Zhang, M., Tang, H., Cao, X. Blood (2005) [Pubmed]
  20. Distinct temporal patterns of macrophage-inflammatory protein-2 and KC chemokine gene expression in surgical injury. Endlich, B., Armstrong, D., Brodsky, J., Novotny, M., Hamilton, T.A. J. Immunol. (2002) [Pubmed]
  21. LPS regulates proinflammatory gene expression in macrophages by altering histone deacetylase expression. Aung, H.T., Schroder, K., Himes, S.R., Brion, K., van Zuylen, W., Trieu, A., Suzuki, H., Hayashizaki, Y., Hume, D.A., Sweet, M.J., Ravasi, T. FASEB J. (2006) [Pubmed]
  22. Stat3 in resident macrophages as a repressor protein of inflammatory response. Matsukawa, A., Kudo, S., Maeda, T., Numata, K., Watanabe, H., Takeda, K., Akira, S., Ito, T. J. Immunol. (2005) [Pubmed]
  23. Inosine reduces systemic inflammation and improves survival in septic shock induced by cecal ligation and puncture. Liaudet, L., Mabley, J.G., Soriano, F.G., Pacher, P., Marton, A., Haskó, G., Szabó, C. Am. J. Respir. Crit. Care Med. (2001) [Pubmed]
  24. Generation and functional significance of CXC chemokines for neutrophil-induced liver injury during endotoxemia. Dorman, R.B., Gujral, J.S., Bajt, M.L., Farhood, A., Jaeschke, H. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  25. 17 beta-estradiol inhibits cytokine, chemokine, and chemokine receptor mRNA expression in the central nervous system of female mice with experimental autoimmune encephalomyelitis. Matejuk, A., Adlard, K., Zamora, A., Silverman, M., Vandenbark, A.A., Offner, H. J. Neurosci. Res. (2001) [Pubmed]
  26. Hypoxia induces macrophage inflammatory protein-2 (MIP-2) gene expression in murine macrophages via NF-kappaB: the prominent role of p42/ p44 and PI3 kinase pathways. Zampetaki, A., Mitsialis, S.A., Pfeilschifter, J., Kourembanas, S. FASEB J. (2004) [Pubmed]
  27. Increased pulmonary responses to acute ozone exposure in obese db/db mice. Lu, F.L., Johnston, R.A., Flynt, L., Theman, T.A., Terry, R.D., Schwartzman, I.N., Lee, A., Shore, S.A. Am. J. Physiol. Lung Cell Mol. Physiol. (2006) [Pubmed]
  28. Autocrine action of IL-10 suppresses proinflammatory mediators and inflammation in the HSV-1-infected cornea. Yan, X.T., Zhuang, M., Oakes, J.E., Lausch, R.N. J. Leukoc. Biol. (2001) [Pubmed]
  29. Interleukin-10 mediates the protective effect of Linomide by reducing CXC chemokine production in endotoxin-induced liver injury. Li, X., Klintman, D., Sato, T., Hedlund, G., Schramm, R., Jeppsson, B., Thorlacius, H. Br. J. Pharmacol. (2004) [Pubmed]
  30. Interleukin-10 expression and chemokine regulation during the evolution of murine type II collagen-induced arthritis. Kasama, T., Strieter, R.M., Lukacs, N.W., Lincoln, P.M., Burdick, M.D., Kunkel, S.L. J. Clin. Invest. (1995) [Pubmed]
  31. Toll-like receptor 4 mediates innate immune responses to Haemophilus influenzae infection in mouse lung. Wang, X., Moser, C., Louboutin, J.P., Lysenko, E.S., Weiner, D.J., Weiser, J.N., Wilson, J.M. J. Immunol. (2002) [Pubmed]
  32. Chemokine amplification in mesangial cells. Luo, Y., Lloyd, C., Gutierrez-Ramos, J.C., Dorf, M.E. J. Immunol. (1999) [Pubmed]
  33. Resident cell chemokine expression serves as the major mechanism for leukocyte recruitment during local inflammation. García-Ramallo, E., Marques, T., Prats, N., Beleta, J., Kunkel, S.L., Godessart, N. J. Immunol. (2002) [Pubmed]
  34. Circulating CXC-chemokine concentrations in a murine intestinal ischemia-reperfusion model. Maheshwari, A., Christensen, R.D., Calhoun, D.A., Dimmitt, R.A., Lacson, A. Fetal and pediatric pathology. (2004) [Pubmed]
  35. Mitogenic properties of endogenous and pharmacological doses of macrophage inflammatory protein-2 after 70% hepatectomy in the mouse. Ren, X., Carpenter, A., Hogaboam, C., Colletti, L. Am. J. Pathol. (2003) [Pubmed]
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