In:
American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 305, No. 1 ( 2013-07-01), p. C70-C77
Abstract:
The function of dendritic cells (DCs), antigen-presenting cells regulating naïve T-cells, is regulated by cytosolic Ca 2+ concentration ([Ca 2+ ] i ). [Ca 2+ ] i is increased by store-operated Ca 2+ entry and decreased by K + -independent (NCX) and K + -dependent (NCKX) Na + /Ca 2+ exchangers. NCKX exchangers are stimulated by immunosuppressive 1,25-dihydroxyvitamin D3 [1,25(OH) 2 D 3 ], the biologically active form of vitamin D. Formation of 1,25(OH) 2 D 3 is inhibited by the antiaging protein Klotho. Thus 1,25(OH) 2 D 3 plasma levels are excessive in Klotho-deficient mice ( klotho hm ). The present study explored whether Klotho deficiency modifies [Ca 2+ ] i regulation in DCs. DCs were isolated from the bone marrow of klotho hm mice and wild-type mice ( klotho +/+ ) and cultured for 7–9 days with granulocyte-macrophage colony-stimulating factor. According to major histocompatibility complex II (MHC II) and CD86 expression, differentiation and lipopolysaccharide (LPS)-induced maturation were similar in klotho hm DCs and klotho +/+ DCs. However, NCKX1 membrane abundance and NCX/NCKX-activity were significantly enhanced in klotho hm DCs. The [Ca 2+ ] i increase upon acute application of LPS (1 μg/ml) was significantly lower in klotho hm DCs than in klotho +/+ DCs, a difference reversed by the NCKX blocker 3′,4′-dichlorobenzamyl (DBZ; 10 μM). CCL21-dependent migration was significantly less in klotho hm DCs than in klotho +/+ DCs but could be restored by DBZ. NCKX activity was enhanced by pretreatment of klotho +/+ DC precursors with 1,25(OH) 2 D 3 the first 2 days after isolation from bone marrow. Feeding klotho hm mice a vitamin D-deficient diet decreased NCKX activity, augmented LPS-induced increase of [Ca 2+ ] i , and enhanced migration of klotho hm DCs, thus dissipating the differences between klotho hm DCs and klotho +/+ DCs. In conclusion, Klotho deficiency upregulates NCKX1 membrane abundance and Na + /Ca 2+ -exchange activity, thus blunting the increase of [Ca 2+ ] i following LPS exposure and CCL21-mediated migration. The effects are in large part due to excessive 1,25(OH) 2 D 3 formation.
Type of Medium:
Online Resource
ISSN:
0363-6143
,
1522-1563
DOI:
10.1152/ajpcell.00355.2012
Language:
English
Publisher:
American Physiological Society
Publication Date:
2013
detail.hit.zdb_id:
1477334-X
SSG:
12
Permalink