Bradykinin B2 receptor and dopamine D2 receptor cooperatively contribute to the regulation of neutrophil adhesion to endothelial cells*

  • Anna Niewiarowska-Sendo Jagiellonian University in Krakow
  • Anna Łabędź-Masłowska Jagiellonian University in Krakow
  • Andrzej Kozik Jagiellonian University in Krakow
  • Ibeth Guevara-Lora Jagiellonian University in Krakow


Leukocyte adhesion to the vascular endothelium contributes to many immunological and inflammatory disorders. These processes have been shown to be mediated by bradykinin receptor type 2 (B2R) and dopamine receptor type 2 (D2R). In a previous study, we reported the formation of a B2R-D2R heterodimer, possibly altering cellular functions. Hence, in the present study, we examined the effect of co-activation of endothelial cells with B2R and D2R agonists on the interaction of these cells with neutrophils. Bradykinin, the main B2R agonist, significantly increased cell adhesion, and this effect was reversed when the endothelial cells were additionally co-treated with a selective D2R agonist, sumanirole. These results were dependent on the incubation time, showing an opposite tendency after prolonged stimulation. Significant changes in the expression of adhesion proteins, such as E-selectin and intracellular adhesion molecule 1 in endothelial cells were observed. Additionally, the cells preincubated with tumor necrosis factor-a showed decreased cell adhesion and IL-8 release after long incubation with both agonists. The modulation of cell adhesion by D2R and B2R seem to be mediated via STAT3 phosphorylation. In summary, this study demonstrated a protective role of D2R in neutrophil-endothelial cell adhesion induced by bradykinin, especially in cytokine-stimulated endothelial cells.

Author Biographies

Anna Niewiarowska-Sendo, Jagiellonian University in Krakow
Faculty of Biochemistry, Biophysics and Biotechnology, Department of Analitycal Biochemistry
Anna Łabędź-Masłowska, Jagiellonian University in Krakow
Faculty of Biochemistry, Biophysics and Biotechnology, Department of Cell Biology
Andrzej Kozik, Jagiellonian University in Krakow
Faculty of Biochemistry, Biophysics and Biotechnology, Department of Analitycal Biochemistry
Ibeth Guevara-Lora, Jagiellonian University in Krakow
Faculty od Biochemistry, Biophysics and Biotechnology, Department of Analitycal Biochemistry


Besser MJ, Ganor Y, Levite M (2005) Dopamine by itself activates either D2, D3 or D1/D5 dopaminergic receptors in normal human T-cells and triggers the selective secretion of either IL-10, TNFalpha or both. J Neuroimmunol 169: 161-171.

Bhoola K.D., Figueroa C.D., Worthy K. (1992). Bioregulation of kinins: kallikreins, kininogens and kininases. Pharmacol Rev 44: 1-80.

Blais CJ, Marceau F, Rouleau JL, Adam A (2000) The kallikrein-kininogen-kinin system: lessons from the quantification of endogenous kinins. Peptides 21: 1903-1940.

Ferre S, Casado V, Devi LA, Filizola M, Jockers R, Lohse MJ, Milligan G, Pin JP, Guitart X (2014) G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives. Pharmacol Rev 66: 413-434.

Figueroa CD, Matus CE, Pavicic F, Sarmiento J, Hidalgo MA, Burgos RA, Gonzalez CB, Bhoola KD, Ehrenfeld P (2015) Kinin B1 receptor regulates interactions between neutrophils and endothelial cells by modulating the levels of Mac-1, LFA-1 and intercellular adhesion molecule-1. Innate Immun 21: 289-304.

Gharavi NM, Alva JA, Mouillesseaux KP, Lai C, Yeh M, Yeung W, Johnson J, Szeto WL, Hong L, Fishbein M, Wei L, Pfeffer LM, Berliner JA (2007) Role of the Jak/STAT pathway in the regulation of interleukin-8 transcription by oxidized phospholipids in vitro and in atherosclerosis in vivo. J Biol Chem 282: 31460-31468.

Guevara-Lora I, Florkowska M, Kozik A (2009) Bradykinin-related peptides up-regulate the expression of kinin B1 and B2 receptor genes in human promonocytic cell line U937. Acta Biochim Pol. 56: 515-522.

Guevara-Lora I, Labedz A, Skrzeczynska-Moncznik J, Kozik A (2011) Bradykinin and des-Arg10-kallidin enhance the adhesion of polymorphonuclear leukocyes to extracellular matrix proteins and endothelial cells. Cell Adhes Commun 18: 67-71.

Guevara-Lora I, Stalinska K, Augustynek B, Labedz-Maslowska A (2014) Influence of kinin peptides on monocyte-endothelial cell adhesion. J Cell Biochem 115: 1985-1995.

Guevara-Lora I, Niewiarowska-Sendo A, Polit A, Kozik A (2016) Hypothetical orchestrated cooperation between dopaminergic and kinin receptors for the regulation of common functions. Acta Biochim Pol 63: 387-396.

Horke S, Witte I, Wilgenbus P, Kruger M, Strand D, Forstermann U (2007) Paraoxonase-2 reduces oxidative stress in vascular cells and decreases endoplasmic reticulum stress-induced caspase activation. Circulation 115: 2055-2064.

Ishihara K, Kamata M, Hayashi I, Yamashina S, Majima M (2002) Roles of bradykinin in vascular permeability and angiogenesis in solid tumor. Int Immunopharmacol 2: 499-509.

Ju H, Venema VJ, Liang H, Harris MB, Zou R, Venema RC (2000) Bradykinin activates the Janus-activated kinase/signal transducers and activators of transcription (JAK/STAT) pathway in vascular endothelial cells: localization of JAK/STAT signalling proteins in plasmalemmal caveolae. Biochem J 351: 257-264.

Kang DS, Ryberg K, Morgelin M, Leeb-Lundberg LMF (2004) Spontaneous formation of a proteolytic B1 and B2 bradykinin receptor complex with enhanced signaling capacity. J Biol Chem 279: 22102–22107.

Kim KS, Yoon YR, Lee HJ, Yoon S, Kim SY, Shin SW, An JJ, Kim MS, Choi SY, Sun W, Baik JH (2010) Enhanced hypothalamic leptin signaling in mice lacking dopamine D2 receptors. J Biol Chem 285: 8905-8917.

Kim KJ, Kwon SH, Yun JH, Jeong HS, Kim HR, Lee EH, Ye SK, Cho CH (2017) STAT3 activation in endothelial cells is important for tumor metastasis via increased cell adhesion molecule expression. Oncogene 36: 5445-5459.

Konkalmatt PR, Asico LD, Zhang Y, Yang Y, Drachenberg C, Zheng X, Han F, Jose PA, Armando I (2016) Renal rescue of dopamine D2 receptor function reverses renal injury and high blood pressure. JCI Insight 1: e85888.

Koyama S, Sato E, Numanami H, Kubo K, Nagai S, Izumi T (2000) Bradykinin stimulates lung fibroblasts to release neutrophil and monocyte chemotactic activity. Am J Respir Cell Mol Biol 22: 75-84.

Langer HF, Chavakis T (2009) Leukocyte-endothelial interactions in inflammation. J Cell Mol Med 13: 1211-1220.

Leeb-Lundberg LM, Marceau F, Muller-Esterl W, Pettibone DJ, Zuraw BL (2005) International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. Pharmacol Rev 57: 27-77.

Lehmberg J, Beck J, Baethmann A, Uhl E (2003) Bradykinin antagonists reduce leukocyte-endothelium interactions after global cerebral ischemia. J Cereb Blood Flow Metab 23: 441-448.

McCall RB, Lookingland KJ, Bedard PJ, Huff RM (2005) Sumanirole, a highly dopamine D2-selective receptor agonist: in vitro and in vivo pharmacological characterization and efficacy in animal models of Parkinson's disease. J Pharmacol Exp Ther 314: 1248–1256.

Mestas J, Ley K (2008) Monocyte- endothelial cell interactions in the development of atherosclerosis. Trends Cardiovasc Med 18: 228-232.

Missale C, Nash SR, Robinson SW, Jaber M Caron MG (1998) Dopamine receptors: from structure to function. Physiol Rev 78: 189–225.

Niewiarowska-Sendo A, Polit A, Piwowar M, Tworzydło M, Kozik A, Guevara-Lora I (2017) Bradykinin B2 and dopamine D2 receptors form a functional dimer. Biochim Biophys Acta 1864: 1855-1866.

Panes J, Perry M, Granger DN (1999) Leukocyte-endothelial cell adhesion: avenues for therapeutic intervention. Br J Pharmacol 126: 537-550.

Qiu J, Yan Z, Tao K, Li Y, Li Y, Li J, Dong Y, Feng D, Chen H (2016) Sinomenine activates astrocytic dopamine D2 receptors and alleviates neuroinflammatory injury via the CRYAB/STAT3 pathway after ischemic stroke in mice. J Neuroinflammation 13: 263.

R Core Team (2016) R: A language and environment for statistical computing, R Foundation for Statistical Computing, Vienna, Austria.

Roscioni SS, Kistemaker LE, Menzen MH, Elzinga CR, Gosens R,Halayko AJ, Meurs H, Schmidt M (2009) PKA and Epac cooperate to augment bradykinin-induced interleukin-8 release from human airway smooth muscle cells. Respir Res 10: 88.

Scholz D, Devaux B, Hirche A, Pötzsch B, Kropp B, Schaper W, Schaper J (1996) Expression of adhesion molecules is specific and time-dependent in cytokine-stimulated endothelial cells in culture. Cell Tissue Res. 284: 415-423.

Schuschke DA, Saari JT, Miller FN (2001) Leukocyte-endothelial adhesion is impaired in the cremaster muscle microcirculation of the copper-deficient rat. Immunol Lett 76: 139-144.

Shigematsu S, Ishida S, Gute DC, Korthuis RJ (2002) Bradykinin-induced proinflammatory signaling mechanisms. Am J Physiol Heart Circ Physiol 283: H2676-H2686.

Su JB (2015) Vascular endothelial dysfunction and pharmacological treatment. World J Cardiol 7: 719-741.

Terzuoli E, Meini S, Cucchi P, Catalani C, Cialdai C, Maggi CA, Giachetti A, Ziche M, Donnini S (2014) Antagonism of bradykinin B2 receptor prevents inflammatory responses in human endothelial cells by quenching the NF-kB pathway activation. PLoS One 9: e84358.

Wei Z, Jiang W, Wang H, Li H, Tang B, Liu B, Jiang H, Sun X (2018) The IL-6/STAT3 pathway regulates adhesion molecules and cytoskeleton of endothelial cells in thromboangiitis obliterans. Cell Signal 44: 118-126.

Zarei S, Frieden M, Rubi B, Villemin P, Gauthier BR, Maechler P, Vischer UM (2006) Dopamine modulates von Willebrand factor secretion in endothelial cells via D2-D4 receptors. J Thromb Haemost 4: 1588-1595.

Zawrotniak M, Bochenska O, Karkowska-Kuleta J, Seweryn-Ozog K, Aoki W, Ueda M, Kozik A, Rapala-Kozik M (2017) Aspartic Proteases and Major Cell Wall Components in Candida albicans Trigger the Release of Neutrophil Extracellular Traps. Front Cell Infect Microbiol 7: 414.

Zhang Y, Cuevas S, Asico LD, Escano C, Yang Y, Pascua AM, Wang X, Jones JE, Grandy D, Eisner G, Jose PA, Armando I (2012) Deficient dopamine D2 receptor function causes renal inflammation independently of high blood pressure. PLoS One 7: e38745.

Zhang Y, Chen Y, Wu J, Manaenko A, Yang P, Tang J, Fu W, Zhang JH (2015) Activation of Dopamine D2 Receptor Suppresses Neuroinflammation Through αB-Crystalline by Inhibition of NF-κB Nuclear Translocation in Experimental ICH Mice Model. Stroke 46: 2637-2646.