J Immunol. 2006 Feb 15;176(4):2337-45. Immunology.
2006 Jan;117(1):89-96. Liver Transpl. 2006 Feb;12(2):247-52.
Chemokine receptor CXCR3 desensitization by IL-16/CD4
signaling is dependent on CCR5 and intact membrane cholesterol.
Rahangdale
S, Morgan R, Heijens
C, Ryan TC, Yamasaki H,
Bentley E,
Sullivan E,
Center DM,
Cruikshank
WW.
Pulmonary Center,
Previous work has shown that IL-16/CD4 induces desensitization of both
CCR5- and CXCR4-induced migration, with no apparent effect on CCR2b or
CCR3. To investigate the functional relationship between CD4 and other chemokine receptors, we determined the effects of IL-16
interaction with CD4 on CXCR3-induced migration. In this study we
demonstrate that IL-16/CD4 induced receptor desensitization of CXCR3 on
primary human T cells. IL-16/CD4 stimulation does not result in surface
modulation of CXCR3 or changes in CXCL10 binding affinity. This effect does
require p56(lck)
enzymatic activity and the presence of CCR5, because desensitization is not
transmitted in the absence of CCR5. Treatment of human T cells with
methyl-beta-cyclodextrin, a cholesterol chelator, prevented the desensitization of CXCR3 via
IL-16/CD4, which was restored after reloading of cholesterol, indicating a
requirement for intact cholesterol. These studies demonstrate an intimate
functional relationship among CD4, CCR5, and CXCR3, in which CCR5 can act
as an adaptor molecule for CD4 signaling. This process of regulating Th1
cell chemoattraction may represent a mechanism
for orchestrating cell recruitment in Th1-mediated diseases.
Interleukin-16 inhibits interleukin-13
production by allergen-stimulated blood mononuclear cells.
El Bassam S, Pinsonneault
S, Kornfeld
H, Ren
F, Menezes
J, Laberge
S.
Laboratory of Immunology,
Expression of interleukin (IL)-16 is increased in bronchial mucosal
biopsies of atopic asthmatics compared to normal
controls. The functional significance of increased expression of IL-16 at
sites of allergic inflammation is not yet clear. We have previously shown
that IL-16 inhibits IL-5 secretion by allergen-stimulated peripheral blood
mononuclear cells (PBMC). We investigated whether IL-16 inhibits the
production of other T helper 2 cytokines, namely IL-13 and IL-4, by allergen-specific
T cells. PBMC from ragweed-sensitive atopic
subjects were stimulated with allergen extract for cytokine production in
the presence or absence of rhIL-16. Production of cytokines was assessed by
enzyme-linked immunosorbent assay and reverse
transcription-polymerase chain reaction. To evaluate whether the modulatory effect of IL-16 on cytokine synthesis was
mediated by interferon-gamma (IFN-gamma), IL-10, IL-12 or IL-18,
allergen-stimulated PBMC were cultured in presence of IL-16 and
neutralizing concentrations of relevant antibodies. Allergen-stimulated
PBMC produced significantly elevated levels of IL-13 (90-740 pg/ml) as
compared to unstimulated PBMC (0-375 pg/ml, P
< 0.01). Addition of rhIL-16 resulted in down-regulation of IL-13 mRNA
expression as well as significantly reduced amounts of IL-13 released by
allergen-stimulated PBMC (0-457 pg/ml, P < 0.001), as observed for IL-5.
No effect of IL-16 was observed on IL-4 mRNA expression. Treatment with
IL-16 resulted in increased levels of IL-10 and IL-18 in
allergen-stimulated cell culture. Neutralization of IFN-gamma, IL-12, IL-10
or IL-18 did not alter the inhibitory effects of IL-16 on IL-13 and IL-5
secretion by allergen-stimulated PBMC. IL-16 did not modify IL-13 synthesis
by anti-CD3-stimulated CD4(+) T cells, but it
significantly reduced the production of IL-5. These data suggest that IL-16
may play an important immunoregulatory role in
allergic states in response to allergen.
PMID: 16423044 [PubMed - indexed for MEDLINE]
Allograft TNFbeta
and IL16 polymorphisms influence HCV recurrence and severity after liver
transplantation.
Kimball P,
Baker M, Fisher RA.
Department of Surgery, Medical College of Virginia Hospitals at Virginia
Commonwealth University, Richmond, VA 23298, USA. pkimball@gems.vcu.edu
Hepatitis C (HCV) recurrence after liver transplantation is universal
although severity varies. We explored whether certain donor cytokine gene
polymorphisms may be useful markers of susceptibility to severe recurrence.
Allograft tumor necrosis factor (TNF) beta and interleukin (IL) 16 gene
polymorphisms were correlated with l-yr clinical outcome among HCV+
recipients. Recipients of donor TNFbeta(2,2) (n = 8) experienced less recurrence (50% vs. 71%,
P < 0.05), less fibrosis (25% vs. 76%, P < 0.01), and less rejection
(25% vs. 71%, P < 0.01) than donor TNFbeta(1,1)
(n = 19). Recipients of donor TNFbeta(1,2) (n = 27) demonstrated an intermediate picture with
less fibrosis (56%, P < 0.01) and less rejection (37%, P < 0.01) than
TNFbeta(1,1). Recipients with donor IL16(TC) (n = 22) showed less recurrence (65% vs. 78%, P
= 0.05), less fibrosis (53% vs. 67%, P = 0.06), and less rejection (41% vs.
55%, P = 0.06) than IL16(TT) (n = 32) genotype. Recipients of the
combination TNFbeta(2,2)/IL16(TC) donor genotype had the most benign
clinical outcome with less recurrence (33% vs. 75%, P < 0.01), no
fibrosis (0% vs. 50%, P < 0.001), and fewer rejections (33% vs. 75%, P
< 0.01) than donor TNFbeta(1,1)/IL16(TT)
genotype. In vitro production of cytokines correlated with genotype. Release
of soluble TNFbeta for TNFbeta(1,1) vs. TNFbeta(1,2) and TNFbeta(2,2)
was 4803 +/- 2142 pg/mL vs. 5629 +/- 3106 (P =
not significant [ns]) and 7180 +/- 3005 (P = ns). Release of soluble IL16
for IL16(TT) vs. IL16(TC) was 437 +/- 86 pg/mL vs. 554 +/- 39 (P = 0.06). In conclusion, allograft TNFbeta and IL16 gene polymorphisms may be useful
markers to predict the severity of disease recurrence among HCV+ patients
after liver transplantation. Copyright 2006 AASLD
PMID: 16447204 [PubMed - in process]