<<Disclaimer: Verify this information before applying it to your situation.>>
Move over Dr. Fasano... It seems Dr. Fasano is not alone in studying
intestinal permeability and its relation to autoimmune diseases. The
following March 2005 International Journal of Molecular Medicine looks at
tight junction proteins (including zonulin) and Crohn's disease. Even more
interesting is the involvement of transforming growth factor, TGF-beta, in
regulating permeability. That got me thinking. I have previously
discussed the how levels of TGF-beta1 and Th3 helper T cells affect food
allergies and celiac disease, and that probiotic strains of the bacteria,
L. paracasei, can stimulate Th3 cell generation, increase TGF-beta1 levels,
and reduce allergies. See:
http://maelstrom.stjohns.edu/CGI/wa.exe?A2=ind0501e&L=celiac&P=2666
http://maelstrom.stjohns.edu/CGI/wa.exe?A2=ind0502a&L=celiac&P=164
http://maelstrom.stjohns.edu/CGI/wa.exe?A2=ind0502a&L=celiac&P=9694
http://maelstrom.stjohns.edu/CGI/wa.exe?A2=ind0502a&L=celiac&P=9818
Further research, focusing on sperm production, looks at Sertoli cell tight
junctions that constitute the blood-testis barrier. TGF-beta3 is shown to
regulate the permeability of this tight junction, possibly by inhibiting
zonulin. (See abstracts below.)
So, can regulating and altering levels of TGF-beta proteins inhibit zonulin
in the same way as AT-1001 to achieve a reduction of "leaky gut"? Or, in
other words, can a probiotic achieve the same effect as AT-1001 to inhibit
zonulin? This might save us a fortune in pharmaceutical costs...
----------
Int J Mol Med. 2005 Mar;15(3):407-10.
Dislocation of tight junction proteins without F-actin disruption in
inactive Crohn's disease.
Oshitani N, Watanabe K, Nakamura S, Fujiwara Y, Higuchi K, Arakawa T.
Third Department of Internal Medicine, Osaka City University Medical
School, Abeno-ku, Osaka 545-8585, Japan. [log in to unmask]
Crohn's disease is associated with increased permeability of the intestinal
barrier even in quiescent patients. Increased intestinal permeability may
cause dysregulated immunological responses in the intestinal mucosa that
leads to chronic intestinal inflammation. We have studied the expression of
tight junction proteins (occludin and zonula occludens), alpha2-smooth
muscle actin, TGF-beta with a cytoskeletal protein (F-actin) in the
intestinal epithelium of patients with inflammatory bowel disease. Surgical
samples were obtained from 6 controls (individuals without inflammatory
bowel disease), 8 patients with ulcerative colitis and 7 patients with
Crohn's disease. F-actin was visualized with fluorescein phalloidin. Tight
junction proteins, alpha2 smooth muscle actin, and TGFbeta were visualized
by the immunofluorescent method. Occludin and zonula occludens found in
apical tight junctions in normal epithelium were dislocated to the
basolateral position and in the lamina propria extracellular matrix in
patients with Crohn's disease, while the structure of F-actin was
maintained in inactive or minimally inflamed mucosa. TGF-beta positive
inflammatory cells were increased in ulcerative colitis and Crohn's disease
mucosa. Subepithelial myofibroblasts were constitutively found in controls,
ulcerative colitis, and Crohn's disease mucosa. Latent dislocation of tight
junction proteins, without disturbance of the cytoskeleton in the inactive
mucosa of patients with Crohn's disease, may permit the invasion of gut
antigens because the functional disruption of tight junctions could
initiate an altered immune response.
PMID: 15702229 [PubMed - in process]
----------
J Cell Biol. 2003 Dec 22;163(6):1303-11.
Free full text:
http://www.jcb.org/cgi/content/full/163/6/1303
TGF-beta receptor kinase inhibitor enhances growth and integrity of
embryonic stem cell-derived endothelial cells.
Watabe T, Nishihara A, Mishima K, Yamashita J, Shimizu K, Miyazawa K,
Nishikawa S, Miyazono K.
Department of Molecular Pathology, Graduate School of Medicine, The
University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan.
Recent findings have shown that embryonic vascular progenitor cells are
capable of differentiating into mural and endothelial cells. However, the
molecular mechanisms that regulate their differentiation, proliferation,
and endothelial sheet formation remain to be elucidated. Here, we show that
members of the transforming growth factor (TGF)-beta superfamily play
important roles during differentiation of vascular progenitor cells derived
from mouse embryonic stem cells (ESCs) and from 8.5-days postcoitum
embryos. TGF-beta and activin inhibited proliferation and sheet formation
of endothelial cells. Interestingly, SB-431542, a synthetic molecule that
inhibits the kinases of receptors for TGF-beta and activin, facilitated
proliferation and sheet formation of ESC-derived endothelial cells.
Moreover, SB-431542 up-regulated the expression of claudin-5, an
endothelial specific component of tight junctions. These results suggest
that endogenous TGF-beta/activin signals play important roles in regulating
vascular growth and permeability.
PMID: 14676305 [PubMed - indexed for MEDLINE]
----------
Endocrinology. 2001 May;142(5):1865-77.
Free full text:
http://endo.endojournals.org/cgi/content/full/142/5/1865
Transforming growth factor-beta3 perturbs the inter-Sertoli tight junction
permeability barrier in vitro possibly mediated via its effects on
occludin, zonula occludens-1, and claudin-11.
Lui WY, Lee WM, Cheng CY.
Population Council, Center for Biomedical Research, New York, New York
10021, USA.
Throughout spermatogenesis, inter-Sertoli tight junctions (TJs) that create
the blood-testis barrier in the rat must be disassembled and reassembled to
permit the timely passage of preleptotene spermatocytes from the basal to
the adluminal compartment of the seminiferous epithelium. However, the
mechanism(s) and the participating molecules that regulate this event are
largely unknown. Although there is no in vitro model to study the event and
regulation of inter-Sertoli TJ disassembly, primary cultures of Sertoli
cells in vitro can be used to study junction assembly. In this study, we
sought to investigate whether cytokines are involved in the inter-Sertoli
TJ assembly in vitro. Sertoli cells isolated from 20-day-old rats were
cultured at a density of 0.5-1.2 x 10(6) cells/cm(2) on Matrigel-coated
dishes or bicameral units for 8-9 days. The steady-state messenger RNA
levels of basic fibroblast growth factor (bFGF), transforming growth factor
(TGF)-beta2, and TGF-beta3 at different time points were assessed by
semiquantitative RT-PCR. In selected experiments, the assembly of inter-
Sertoli TJs was monitored by transepithelial electrical resistance
measurement. It was found that there was no change in the expression of
basic fibroblast growth factor throughout the entire culture period.
However, there was a 2-fold reduction in the expression of TGF-beta2 and
TGF-beta3 at the time inter-Sertoli TJs were being assembled. On days 5-8,
after the inter-Sertoli TJs had been assembled, the Sertoli cell steady-
state messenger RNA levels of TGF-beta2 and TGF-beta3 increased by as much
as 3- and 6-fold, respectively, when compared with Sertoli cells on days 1-
3 when TJs were being assembled. Also, it was found that recombinant TGF-
beta3 added to Sertoli cells cultured in vitro at 1.2 x 10(6) cells/cm(2)
on Matrigel-coated bicameral units perturbed the inter-Sertoli TJ
permeability barrier dose-dependently. Moreover, the presence of TGF-beta3
also inhibited the transient and/or basal expression of several TJ-
associated proteins, which include occludin, zonula occludens-1, and
claudin-11 when inter-Sertoli TJs were being assembled in vitro. These
results suggest that TGF-beta plays a crucial role in regulating the
complicated biochemical events of junction assembly in the testis.
PMID: 11316752 [PubMed - indexed for MEDLINE]
----------
Biol Reprod. 2003 May;68(5):1597-612. Epub 2002 Nov 27.
Free full text:
http://www.biolreprod.org/cgi/content/full/68/5/1597
Transforming growth factor beta3 regulates the dynamics of Sertoli cell
tight junctions via the p38 mitogen-activated protein kinase pathway.
Lui WY, Lee WM, Cheng CY.
Population Council, Center for Biomedical Research, New York, New York
10021, USA.
Earlier studies have implicated the significance of transforming growth
factor-beta3 (TGFbeta3) in the regulation of Sertoli cell tight junction
(TJ) dynamics, possibly via its inhibitory effects on the expression of
occludin, claudin-11, and zonula occludens-1 (ZO-1). Yet the mechanism by
which TGFbeta3 regulates the Sertoli cell TJ-permeability barrier is not
known. Using techniques of semiquantitative reverse transcription-PCR (RT-
PCR), immunoblotting, immunohistochemistry, and inhibitors against
different kinases coupled with physiological techniques to assess the
Sertoli cell TJ barrier function, it was shown that this TGFbeta3-induced
effect on Sertoli cell TJ dynamics is mediated via the p38 mitogen-
activated protein (MAP) kinase pathway. First, the assembly of the Sertoli
cell-TJ barrier was shown to be associated with a transient but significant
decline in both the TGFbeta3 production and expression by Sertoli cells.
Furthermore, addition of TGFbeta3 to Sertoli cell cultures during TJ
assembly indeed perturbed the TJ barrier with an IC50 at approximately 9
pM. Second, the TGFbeta3-induced disruption of the TJ barrier was
associated with a transient induction in MEKK2 but not the other upstream
signaling molecules that mediate TGFbeta3 action, such as Smad2, Cdc42,
Rac2, and N-Ras, suggesting this effect might be mediated via the p38 MAP
kinase pathway. This postulate was confirmed by the observation that
TGFbeta3 also induced the protein level of the activated and phosphorylated
form of p38 MAP kinase at the time the TJ barrier was perturbed. Third, and
perhaps the most important of all, this TGFbeta3-mediated inhibitory effect
on the TJ barrier and the TGFbeta3-induced p-p38 MAP kinase production
could be blocked by SB202190, a specific p38 MAP kinase inhibitor, but not
U0126, a specific MEK1/2 kinase inhibitor. These results thus unequivocally
demonstrate that TGFbeta3 utilizes the p38 MAP kinase pathway to regulate
Sertoli cell TJ dynamics.
PMID: 12606350 [PubMed - indexed for MEDLINE]
* * *
*Support summarization of posts, reply to the SENDER not the CELIAC List*
|
