Infection-Induced Kinin B1 Receptors in Human Pulmonary Fibroblasts: Role of Intact Pathogens and p38 Mitogen-Activated Protein Kinase-Dependent Signaling

Abstract

Kinin B 1 receptors (B 1 R) are involved in many pathophysiological processes, and its expression is up-regulated in inflammatory pulmonary disease. Although bacteria can generate kinin peptides, the molecular signaling mechanisms regulating B 1 R during infection by intact pathogens is unknown. The serious opportunistic clinical isolate Burkholderia cenocepacia (B. cen.) belongs to the important B. cepacia complex (Bcc) of gramnegative pathogens that rapidly causes fatal pulmonary disease in hospitalized and immunocompromised patients and those with cystic fibrosis. We demonstrate here that B. cen. infection induced a rapid increase in B 1 R mRNA (1 h) proceeded by an increase in B 1 R protein expression (2 h), without affecting B 2 receptor expression in human pulmonary fibroblasts. The B 1 R response was dose-dependent and maximal by 6 to 8 h (3-to 4-fold increase), however, brief B. cen. infection could sustain B 1 R up-regulation. In contrast, nonclinical Bcc phytopathogens were much less B 1 R inducive. The protein synthesis inhibitor cycloheximide and transcriptional inhibitor actinomycin D abrogated the B 1 response to B. cen. indicating de novo B 1 R synthesis. B. cen. activated p38 mitogen-activated protein kinase (MAPK), and blocking p38 MAPK with the specific inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB 203580) dramatically reduced B. cen.-induced B 1 R. Furthermore, B. cen. regulation of B 1 R was diminished by the anti-inflammatory glucocorticoid dexamethasone. In conclusion, this study is the first demonstration that infection with intact pulmonary pathogens like B. cen. positively modulates the selective expression of B 1 R. Thus, providing evidence that B 1 R regulation may be an important and novel mechanism in the inflammatory cascade in response to chronic pulmonary infection and disease.

Involvement of Extracellular Signal-Regulated Kinase 5 in Kinin B1 Receptor Upregulation in Isolated Human Umbilical Veins

“…In agreement with our results, in vitro studies in rat portal veins , human fetal lung fibroblasts (Phagoo et al, 2005), human lung fibroblasts (Haddad et al, 2000), osteoblastic osteosarcoma cell lines (Brechter et al, 2008), and murine tracheae (Zhang et al, 2007) demonstrated that ERK1/2 inhibition did not result in a significant reduction of kinin B 1 receptor upregulation process.…”

“…In relation to JNK, Medeiros et al (2004) have demonstrated in rat portal veins the relevance of this kinase in the kinin B 1 receptor upregulation process. In human tissues, involvement of these kinases was observed only in osteoblastic osteosarcoma cell lines (Brechter et al, 2008) and fetal lung fibroblast (Phagoo et al, 2005), but it is important to mention that although all these experiments evaluated the kinin B 1 receptor upregulation by radioligand binding assays or qRT-PCR, they did not demonstrate a functional correlation of this phenomenon. In the present study, we demonstrated that the CRCs to DAKD after 5 hours of incubation were inhibited in a dose-dependent manner by continuous incubation with p38 MAPK and JNK selective inhibitors, and this evidence correlated with a significant reduction in kinin B 1 receptor mRNA expression after 5-hour in vitro incubation with these inhibitors in HUVs.…”

“…ERK5, the relatively recently identified MAPK, is able to induce and regulate several physiological processes, including proliferation, angiogenesis, immunologic processes, and stress responses (Plotnikov et al, 2011); however, less information is available about this kinase than about the other MAPK pathways, and the full scope of its functions is not clear. In this sense, whereas many researchers have postulated p38 MAPK, ERK1/2, and JNK as signaling pathways involved in the upregulation of kinin B 1 receptors (Larrivée et al, 1998;Medeiros et al, 2004;Zhang et al, 2004;Phagoo et al, 2005;El Sayah et al, 2006;Brechter et al, 2008), there is still no evidence involving ERK5 in kinin B 1 receptor upregulation. The aim of this study was to evaluate the involvement of ERK5 and the other MAPK signaling pathways in the kinin B 1 receptor upregulation process in our isolated HUV experimental model using together both functional and molecular methods.…”

MAPK/NF-κB-dependent upregulation of kinin receptors mediates airway hyperreactivity: A new perspective for the treatment

“…Dexamethasone strongly inhibits overexpression of inflammatory mediators in the airway cells [121] and AHR to kinins [38,116,121]. In cultured canine tracheal smooth muscle cells, inhibition of ERK1/2 MAPK by PD98059 attenuates TNF-␣- [122], IL-1␤- [123] and LPS- [124] induced kinin B 2 receptor upregulation, and in cultured human lung fibroblasts, p38 inhibitor SB203580 and dexamethasone abrogate infectioninduced kinin B 1 receptor expression [99]. Taken all together, these results strongly suggest that MAPK/NF-B-dependent kinin receptor upregulation might be responsible for the development of AHR and airway inflammation.…”

“…The kinin B 1 receptor is absent under normal conditions, while it is induced following tissue injury [36,98] or after treatment with bacterial endotoxins such as LPS [26,99] or inflammatory mediators such as IL-1␤ [100] or TNF-␣ [70]. Lysdes-Arg 9 -bradykinin (Des-Arg 9 -kallidin) and des-Arg 9 -bradykinin, metabolites of kallidin and bradykinin, selectively act on the kinin B 1 receptor and can be antagonized by the antagonists [Leu 8 ][desArg 9 ]-bradykinin (pA 2 or pK B 6.3-7.5) and [des-Arg 10 ]HOE140 (pA 2 or pK B 6.8-7.2) [101].…”