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IL ‐4 and IL ‐13 inhibit IL ‐1β and TNF ‐α induced kinin B 1 and B 2 receptors through a STAT6 ‐dependent mechanism
Author(s) -
Souza PPC,
Brechter AB,
Reis RI,
Costa CAS,
Lundberg P,
Lerner UH
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12116
Subject(s) - kinin , bradykinin , receptor , endocrinology , chemistry , bone resorption , agonist , medicine , tumor necrosis factor alpha , interleukin , cytokine , microbiology and biotechnology , biology
Background and Purpose Bone resorption induced by interleukin‐1β ( IL ‐1β) and tumour necrosis factor ( TNF ‐α) is synergistically potentiated by kinins, partially due to enhanced kinin receptor expression. Inflammation‐induced bone resorption can be impaired by IL ‐4 and IL ‐13. The aim was to investigate if expression of B 1 and B 2 kinin receptors can be affected by IL ‐4 and IL ‐13. Experimental Approach We examined effects in a human osteoblastic cell line ( MG ‐63), primary human gingival fibroblasts and mouse bones by IL ‐4 and IL ‐13 on mRNA and protein expression of the B 1 and B 2 kinin receptors. We also examined the role of STAT6 by RNA interference and using Stat6 ‐/‐ mice. Key Results IL ‐4 and IL ‐13 decreased the mRNA expression of B 1 and B 2 kinin receptors induced by either IL ‐1β or TNF ‐α in MG ‐63 cells, intact mouse calvarial bones or primary human gingival fibroblasts. The burst of intracellular calcium induced by either bradykinin ( B 2 agonist) or des‐ A rg 10 ‐Lys‐bradykinin ( B 1 agonist) in gingival fibroblasts pretreated with IL ‐1β was impaired by IL ‐4. Similarly, the increased binding of B 1 and B 2 ligands induced by IL ‐1β was decreased by IL ‐4. In calvarial bones from Stat6 ‐deficient mice, and in fibroblasts in which STAT6 was knocked down by siRNA , the effect of IL ‐4 was decreased. Conclusions and Implications These data show, for the first time, that IL ‐4 and IL ‐13 decrease kinin receptors in a STAT6 ‐dependent mechanism, which can be one important mechanism by which these cytokines exert their anti‐inflammatory effects and impair bone resorption.