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Activated human valvular interstitial cells sustain interleukin-17 production to
recruit neutrophils in infective endocarditis
#MMPMID25776751
Yeh CY
; Shun CT
; Kuo YM
; Jung CJ
; Hsieh SC
; Chiu YL
; Chen JW
; Hsu RB
; Yang CJ
; Chia JS
Infect Immun
2015[Jun]; 83
(6
): 2202-12
PMID25776751
show ga
The mechanisms that underlie valvular inflammation in streptococcus-induced
infective endocarditis (IE) remain unclear. We previously demonstrated that
streptococcal glucosyltransferases (GTFs) can activate human heart valvular
interstitial cells (VIC) to secrete interleukin-6 (IL-6), a cytokine involved in
T helper 17 (Th17) cell differentiation. Here, we tested the hypothesis that
activated VIC can enhance neutrophil infiltration through sustained IL-17
production, leading to valvular damage. To monitor cytokine and chemokine
production, leukocyte recruitment, and the induction or expansion of CD4(+)
CD45RA(-) CD25(-) CCR6(+) Th17 cells, primary human VIC were cultured in vitro
and activated by GTFs. Serum cytokine levels were measured using an enzyme-linked
immunosorbent assay (ELISA), and neutrophils and Th17 cells were detected by
immunohistochemistry in infected valves from patients with IE. The expression of
IL-21, IL-23, IL-17, and retinoic acid receptor-related orphan receptor C (Rorc)
was upregulated in GTF-activated VIC, which may enhance the proliferation of
memory Th17 cells in an IL-6-dependent manner. Many chemokines, including
chemokine (C-X-C motif) ligand 1 (CXCL1), were upregulated in GTF-activated VIC,
which might recruit neutrophils and CD4(+) T cells. Moreover, CXCL1 production in
VIC was induced in a dose-dependent manner by IL-17 to enhance neutrophil
chemotaxis. CXCL1-expressing VIC and infiltrating neutrophils could be detected
in infected valves, and serum concentrations of IL-17, IL-21, and IL-23 were
increased in patients with IE compared to healthy donors. Furthermore, elevated
serum IL-21 levels have been significantly associated with severe valvular
damage, including rupture of chordae tendineae, in IE patients. Our findings
suggest that VIC are activated by bacterial modulins to recruit neutrophils and
that such activities might be further enhanced by the production of
Th17-associated cytokines. Together, these factors can amplify the release of
neutrophilic contents in situ, which might lead to severe valvular damage.
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