IL-4 and IL-13 inhibit IL-1β and TNF-α induced kinin B1 and B2 receptors through a STAT6-dependent mechanism.
OBJECTIVE
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 B1 and B2 kinin receptors can be affected by IL-4 and IL-13.


METHODS
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 B1 and B2 kinin receptors. We also examined the role of STAT6 by RNA interference and using Stat6(-/-) mice.


RESULTS
IL-4 and IL-13 decreased the mRNA expression of B1 and B2 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 (B2 agonist) or des-Arg(10) -Lys-bradykinin (B1 agonist) in gingival fibroblasts pretreated with IL-1β was impaired by IL-4. Similarly, the increased binding of B1 and B2 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
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.
Department of Molecular Periodontology, Umeå University, Umeå, Sweden.
P P C
PP
Souza
A B
AB
Brechter
R I
RI
Reis
C A S
CA
Costa
P
P
Lundberg
U H
UH
Lerner
D000818:Animals; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005881:Gingiva / Q000166:cytology; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage; D043783:Receptor, Bradykinin B1 / Q000235:genetics / Q000378:metabolism*; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018793:Interleukin-13; D053583:Interleukin-1beta; D034741:RNA, Small Interfering; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D012313:RNA