Autoregulation of Bradykinin Receptors: Agonists in the Presence of Interleukin-1β Shift the Repertoire of Receptor Subtypes from B2 to B1 in Human Lung Fibroblasts
- 1Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas (S.B.P., L.M.F.L.-L.); and 2Division of Endocrinology, National Institute for Biological Standards and Control, South Mimms, Hertfordshire, United Kingdom (S.P.)
Abstract
Elevated formation of bradykinin (BK) and Lys-BK or kallidin (KD) and their carboxypeptidase metabolites desArg9BK and desArg10KD is evident at sites of inflammation. Moreover, B2 receptors (B2R), which mediate the action of BK and KD, participates in the acute stage of the inflammatory and pain response, whereas B1 receptors (B1R), through which desArg9BK and desArg10KD act, partake in the chronic stage. We hypothesized that kinins autoregulate B2R and B1R expression in favor of B1R. Incubation of IMR-90 cells with BK (100 nM) led to a loss (89%) of B2R with a half-life (T1/2) of 7.0 min. Concomitantly, BK increased B1R (2- to 3-fold) with aT1/2 of 120 min. DesArg10KD (100 nM) had no effect on B2R but increased B1R (3- to 4-fold) with the same rate as BK. Interleukin-1β (IL-1β; 500 pg/ml) also increased B1R (4- to 6-fold). Although both desArg10KD and BK increased the level of IL-1β mRNA, IL-1β receptor antagonist inhibited the increase in B1R only in response to BK. DesArg10KD and BK synergistically increased B1R (9-fold), which was further increased by inclusion of IL-1β (36-fold). Therefore, kinin metabolism and kinin-stimulated production of cytokines may play a pivotal role in shifting the repertoire of kinin receptor subtypes in favor of B1R during inflammation.
Footnotes
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Send reprint requests to: L. M. Fredrik Leeb-Lundberg, Ph.D., Department of Biochemistry, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78284-7760. E-mail:lundberg{at}biochem.uthscsa.edu
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This work was supported by National Institutes of Health Grant GM41659.
- Abbreviations:
- BK
- bradykinin
- KD
- kallidin
- IL
- interleukin
- RT
- reverse transcription
- TNF
- tumor necrosis factor
- PCR
- polymerase chain reaction
- DMEM
- Dulbecco’s modified Eagle’s medium
- IL-1ra
- interleukin-1 receptor antagonist
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- Received March 4, 1999.
- Accepted May 14, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
