Enhanced Ca2+ response and stimulation of prostaglandin release by the bradykinin B2 receptor in human retinal pigment epithelial cells primed with proinflammatory cytokines

Catalioto, Rose‐Marie; Valenti, Claudio; Maggi, Carlo Alberto; Giuliani, Sandro

doi:10.1016/j.bcp.2015.07.034

Cited by 9 publications

(10 citation statements)

References 55 publications

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“…BDKRB1 is absent in most body tissues, but is readily inducible and can be detected when inflammation is present 56 . BDKRB2, on the other hand, is considered to be a constitutive receptor for bradykinin and is highly expressed in all body tissues 56 , although several studies show that it can be further induced under inflammatory conditions 14, 44, 60 .…”

Section: Introductionmentioning

confidence: 99%

A Role for Bradykinin Signaling in Chronic Vulvar Pain

Falsetta

Foster

Woeller

et al. 2016

The Journal of Pain

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Chronic vulvar pain is alarmingly common in women of reproductive age and is often accompanied by psychological distress, sexual dysfunction, and a significant reduction in quality of life. Localized provoked vulvodynia (LPV) is associated with intense vulvar pain concentrated in the vulvar vestibule (area surrounding vaginal opening). To date, the origins of vulvodynia are poorly understood, and treatment for LPV manages pain symptoms, but does not resolve the root causes of disease. Until recently, no definitive disease mechanisms had been identified; our work indicates LPV has inflammatory origins, although additional studies are needed to understand LPV pain. Bradykinin signaling is one of the most potent inducers of inflammatory pain and is a candidate contributor to LPV. We report that bradykinin receptors are expressed at elevated levels in LPV patient versus healthy control vestibular fibroblasts, and patient vestibular fibroblasts produce elevated levels of proinflammatory mediators with bradykinin stimulation. Inhibiting expression of one or both bradykinin receptors significantly reduces proinflammatory mediator production. Finally, we determined that bradykinin activates NFκB signaling (a major inflammatory pathway), while inhibition of NFκB successfully ablates this response. These data suggest that therapeutic agents targeting bradykinin sensing and/or NFκB may represent new, more specific options for LPV therapy. Perspective: There is an unmet need for the development of more effective vulvodynia therapies. As we explore the mechanisms by which human vulvar fibroblasts respond to proinflammatory/pro-pain stimuli, we move closer to understanding the origins of chronic vulvar pain and identifying new therapeutic targets, knowledge which could significantly improve patient care.

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Section: Introductionmentioning

confidence: 99%

A Role for Bradykinin Signaling in Chronic Vulvar Pain

Falsetta

Foster

Woeller

et al. 2016

The Journal of Pain

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“…Production of prostaglandins via BK receptor signaling has been documented in several studies ( 41 , 42 ). A recent study indicates that prostaglandins, especially PGE2 can suppress IFN responses in pDCs ( 43 ).…”

Section: Resultsmentioning

confidence: 99%

Kallikrein–Kinin System Suppresses Type I Interferon Responses: A Novel Pathway of Interferon Regulation

et al. 2018

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The Kallikrein–Kinin System (KKS), comprised of kallikreins (klks), bradykinins (BKs) angiotensin-converting enzyme (ACE), and many other molecules, regulates a number of physiological processes, including inflammation, coagulation, angiogenesis, and control of blood pressure. In this report, we show that KKS regulates Type I IFN responses, thought to be important in lupus pathogenesis. We used CpG (TLR9 ligand), R848 (TLR7 ligand), or recombinant IFN-α to induce interferon-stimulated genes (ISGs) and proteins, and observed that this response was markedly diminished by BKs, klk1 (tissue kallikrein), or captopril (an ACE inhibitor). BKs significantly decreased the ISGs induced by TLRs in vitro and in vivo (in normal and lupus-prone mice), and in human PBMCs, especially the induction of Irf7 gene (p < 0.05), the master regulator of Type I IFNs. ISGs induced by IFN-α were also suppressed by the KKS. MHC Class I upregulation, a classic response to Type I IFNs, was reduced by BKs in murine dendritic cells (DCs). BKs decreased phosphorylation of STAT2 molecules that mediate IFN signaling. Among the secreted pro-inflammatory cytokines/chemokines analyzed (IL-6, IL12p70, and CXCL10), the strongest suppressive effect was on CXCL10, a highly Type I IFN-dependent cytokine, upon CpG stimulation, both in normal and lupus-prone DCs. klks that break down into BKs, also suppressed CpG-induced ISGs in murine DCs. Captopril, a drug that inhibits ACE and increases BK, suppressed ISGs, both in mouse DCs and human PBMCs. The effects of BK were reversed with indomethacin (compound that inhibits production of PGE2), suggesting that BK suppression of IFN responses may be mediated via prostaglandins. These results highlight a novel regulatory mechanism in which members of the KKS control the Type I IFN response and suggest a role for modulators of IFNs in the pathogenesis of lupus and interferonopathies.

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“…The effect of thrombin stimulation on RPE cell [Ca +2 ]i was determined using fluorescence microscopy, as described in the Methods. Although thrombin-induced increase in [Ca +2 ]i in RPE cells has been reported [ 32 , 33 ], the characteristics of this response as a function of the intensity and duration of the stimulus, determinant for functional outcome, have not been analyzed.…”

Section: Resultsmentioning

confidence: 99%

“…Thrombin-induced [Ca 2+ ]i mobilization in RPE cells has been reported [ 32 , 33 ]. Since calpain is a Ca 2+ activated protease, we showed that thrombin induces the specific, dose-dependent increase in [Ca 2+ ]i with an Ec 50 of 0.55 nM ( Figure 1(c) ).…”

Section: Discussionmentioning

confidence: 99%

Thrombin-Induced Calpain Activation Promotes Protease-Activated Receptor 1 Internalization

Alvarez-Arce

Lee-Rivera

López

et al. 2017

International Journal of Cell Biology

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The serine protease thrombin activates Protease-Activated Receptors (PARs), a family of G-protein-coupled receptors (GPCRs) activated by the proteolytic cleavage of their extracellular N-terminal domain. Four members of this family have been identified: PAR1-4. The activation of Protease-Activated Receptor 1(PAR1), the prototype of this receptor family, leads to an increase in intracellular Ca +2 concentration ([Ca +2 ]i) mediated by G q11 coupling and phospholipase C (PLC) activation. We have previously shown that the stimulation of PAR1 by thrombin promotes intracellular signaling leading to RPE cell transformation, proliferation, and migration which characterize fibroproliferative eye diseases leading to blindness. Within this context, the elucidation of the mechanisms involved in PAR1 inactivation is of utmost importance. Due to the irreversible nature of PAR1 activation, its inactivation must be efficiently regulated in order to terminate signaling. Using ARPE-19 human RPE cell line, we characterized thrombininduced [Ca +2 ]i increase and demonstrated the calcium-dependent activation of -calpain mediated by PAR1. Calpains are a family of calcium-activated cysteine proteases involved in multiple cellular processes including the internalization of membrane proteins through clathrin-coated vesicles. We demonstrated that PAR1-induced calpain activation results in the degradation of -spectrin by calpain, essential for receptor endocytosis, and the consequent decrease in PAR1 membrane expression. Collectively, the present results identify a novel -calpain-dependent mechanism for PAR1 inactivation following exposure to thrombin.

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Enhanced Ca2+ response and stimulation of prostaglandin release by the bradykinin B2 receptor in human retinal pigment epithelial cells primed with proinflammatory cytokines

Cited by 9 publications

References 55 publications

A Role for Bradykinin Signaling in Chronic Vulvar Pain

A Role for Bradykinin Signaling in Chronic Vulvar Pain

Kallikrein–Kinin System Suppresses Type I Interferon Responses: A Novel Pathway of Interferon Regulation

Thrombin-Induced Calpain Activation Promotes Protease-Activated Receptor 1 Internalization

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