TNF, IR and psoriasis
eve...@rocketmail.com
Dave,
It is obviously not easy to sort out, beyond doubt, the cause and effect
wrt IR and psoriasis. You believe that psoriasis causes IR via the
production of TNF created from inflamation related to the psoriasis ?
I don't believe this is true. It appears that the amount of serum TNF is
*only* a function of the amount of visceral fat (upper body
triglycerides) and *not* a function of psoriasis or inflamation of any
type.
"These results show that plasma TNF-alpha
levels are essentially dependent on visceral fat
amount, thus suggesting that
TNF-alpha could be one of the factors mediating
insulin resistance and
cardiovascular risk in obese type 2 diabetic
patients."
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&
list_uids=10880890
"In both rodents and man, TNF-alpha is produced in
proportion to the amount of fat available(2)."
http://people.enternet.com.au/~agale/IRbyProietto.htm
So, it seems that visceral triglycerides , which are markers for
Syndrome X are also uniquely neccessary for the existance of TNF and
*not* the other way around, and this tends to strengthen the case that
psoriasis is a disease of Syndrome X. IMO.
We already know that being fat contributes to IR in any case , but it is
not the starting condition for IR. TNF increasing IR in the
hypertriglyceridemic (eg in psoriatics) is thus consistant with this,
but TNF is not the root cause of hypertriglyceridemia or IR or Syndrome
X, and psoriasis on its own has no effect on the levels of serum TNF.
Steve.
Sent via Deja.com http://www.deja.com/
Before you buy.
DaveW
>It is obviously not easy to sort out, beyond doubt, the cause and effect
>wrt IR and psoriasis.
Not without the proper tests, of course.
>You believe that psoriasis causes IR via the
>production of TNF created from inflamation related to the psoriasis ?
>
>I don't believe this is true. It appears that the amount of serum TNF is
>*only* a function of the amount of visceral fat (upper body
>triglycerides) and *not* a function of psoriasis or inflamation of any
>type.
Then you are arguing about something about which you know nothing,
which is something you've taken me to task for in the past. You are
hypocritical beyong belief.
TNF-alpha is a "pro-inflammatory cytokine." It *induces* inflammation.
The two things you cite as evidence,
http://www.pinch.com/skinny?medline=10880890
http://people.enternet.com.au/~agale/IRbyProietto.htm
Are both speaking of TNF-alpha as *produced* by the adipocytes in
overweight people with IR, and *NOT* TNF-alpha produced due to
inflammation.
>So, it seems that visceral triglycerides , which are markers for
>Syndrome X are also uniquely neccessary for the existance of TNF...
"Uniquely necessary?" You really do need to realize that effects
that occur within the body *can* happen due to more than one cause.
Your two cites do *not* claim that TNF-alpha is *only* produced by
"visceral triglycerides."
Your black-and-white world, where only "one-to-one" mappings exist,
doesn't occur in reality. The two examples which come to mind first
are that (A) IR is "almost always" responsible for overweight people,
and (B) high triglycerides are "uniquely necessary" for high TNF. Are
there more? Sure. But they're more off-topic.
Is rheumatoid arthritis a disease of Syndrome X? No. Then why are
Anti-TNF monoclonal antibodies being used to fight it?
http://www.pslgroup.com/dg/145046.htm
How about Encylopedia Britannica?
"...also called CACHECTIN, a naturally occurring protein that is
produced in the human body by the phagocytic cells known as
macrophages. . .TNF seems to perform both helpful and harmful
functions within the body. It helps cause the profound weight loss
(cachexia) seen in some persons suffering from chronic bacterial
and parasitic infections, as well as from cancer. TNF has been
further implicated in the acute circulatory collapse and shock
experienced by some persons who are suffering from acute
bacterial infections. . . But TNF has also been found to play a
much broader (and more positive) role in regulating inflammatory
and immune responses throughout the body..."
Are you sure you want to say that Syndrome X, or even just high
triglyceride levels, is "uniquely necessary" for the existance of TNF in
the blood?
>We already know that being fat contributes to IR in any case , but it is
>not the starting condition for IR. TNF increasing IR in the
>hypertriglyceridemic (eg in psoriatics) is thus consistant with this,
>but TNF is not the root cause of hypertriglyceridemia or IR or Syndrome
>X...
If you'd bother to read my footnotes, you wouldn't be saying these things
at all. TNF-alpha *blocks* the effects of insulin. That is one of the
reasons *why* obesity worsens IR.
The two cites you've provided above do *not* say that TNF is *only*
produced by triglycerides, they say that it's *one way* TNF is increased.
Read up on *just* TNF, without referencing IR for a moment, and learn
all about how TNF is a pro-inflammatory cytokine, type 1, and is made
*mostly* by immune cells, not fat cells.
>...and psoriasis on its own has no effect on the levels of serum TNF.
The medical literature I've cited on my Web page says that you're wrong.
I continue to add cites. I'll add some more for you tonight, perhaps.
Look, you yourself have said that since you have little knowledge of
microbiology, you try to stay away from discussing it. TNF-alpha's
effects on the body are nothing *but* microbiology. If you don't want
to discuss it, then don't. What you've said in this post really indicates
that you are absolutely clueless about TNF, yet you decided to argue
its source. Hypocrite.
- Dave W.
http://members.aol.com/psorsite/
eve...@rocketmail.com
stran...@aol.com (DaveW) wrote:
> Evetsm wrote:
> TNF-alpha is a "pro-inflammatory cytokine." It *induces* inflammation.
Of course TNF is pro-inflamatory, but, *TNF is not produced by
inflamation or psoriasis* ! Can you not see that ? It is not that
difficult. It is a product of triglycerides ie it is only produced by
triglycerides. Those studies I quoted definately say that in so many
words. You have never shown that it is *produced* by psoriasis or
inflamation, because you cannot. You speculated that this was the case
and you are wrong ! Therefore psoriasis cannot produce IR , at least via
TNF ! You cannot see the wood from the trees. Ever ! Did you ever
understand or qualify for anything ?!
This is how it is starting to look. A person with the thrifty genotype,
has a system that is primed to be a super efficient metaboliser of scarce
carbs. Insulin production is on a hair trigger and triglycerides are
super effciently produced from glucose(carbs) conversion. This person
starts scoffing down excess mostly refined carbs and the system goes into
overdrive and the triglycerides (TG's) start mounting and therefore the
TNF starts mounting. The TNF, probably as a biological restraining
factor, starts to induce resistance to the mass of insulin being produced
in an attempt to stem the buildup of triglycerides being produced by the
flood of glucose, by down regulating the PPAR expression. Through at
least this and maybe some other mechanism inflamation is produced by the
TNF, and probably other cytokines, probably also produced by this
situation. The person continues to scoff down carbs and the glucose now *
really* starts mounting in the blood because the isulin action is being
increasingly blocked. The pancreas senses this and starts producing yet
more and more insulin to compensate and attempt to maintain normo-
glycation levels. The circulating insulin(now hyperinsulism),
triglycerides(now hypertryglyceridemia), TNF and therefore IR continue to
mount. You may or may not become obese although you will definitely have
high serum TG's. You are now defined as having the Syndrome X. Depending
on your individual gentic variation this induced inflamation will show up
as "diseases of Syndrome X" ie psoriasis, heart disease, kidney disease,
hypertension PCOS etc or some combination of them.
The TNF fits like a glove into the Syndrome X explanation. It is as a
result of glucose overload and consequent TG production and *not*
produced from psoriasis or inflammation. TNF looks like it contributes to
or even causes, maybe alone maybe not, psoriasis, IR and inflamation.
DaveW
>Of course TNF is pro-inflamatory, but, *TNF is not produced by
>inflamation or psoriasis* ! Can you not see that ? It is not that
>difficult.
Oh, good grief. This proves that you don't read any of the
resources I post for you, yet you expect me to read all of
yours. Hypocrite.
One more time: TNF is produced by the *immune system* cells
to *create* inflammation, including the inflammation which is a
symptom of psoriasis.
>It is a product of triglycerides ie it is only produced by
>triglycerides.
This is nonsense. Triglycerides don't make anything. They are
not cells nor enzymes, they are simple fatty molecules.
This is also contrary to the cite I've shown which says that
while on treatment for psoriasis with etretinate, IR goes away
but the triglyceride levels go *up*. In my theory, the IR goes
away *because* the TNF (and thus the inflammation) of psoriasis
goes away. The high TG levels are a different side-effect of the
drug, uncaused by IR.
>Those studies I quoted definately say that in so many
>words.
No, they don't. *YOU* assume that because adipose tissue
makes TNF, then *nothing else* in the body can. That is
absolutely ridiculous. I posted for you Britannica's entry on
TNF. If you think *that* publication is not reviewed for
accuracy, you are a lunatic.
The first begins,
"TNF-alpha is considered as one of the potential
determinants of insulin resistance. However several data
suggest that TNF-alpha expression itself, could be
modulated by the degree of adiposity and/or plasma
insulin levels."
Then they describe how they tested 16 *diabetic* people and
found a relationship between TNF levels and fat mass. Big
deal. This is *not* TNF that's being created in order to make
inflammation. This is TNF released by adipocytes for whatever
reasons they do so.
The second has this to say:
"Another possible mechanism for fat-induced insulin
resistance independent of the effects of FFAs is the
excess production of the cytokine tumour necrosis
factors (TNF-alpha) from adipocytes."
The author is specifically speaking of TNF produced by
*adipocytes*, in *fat-induced* IR, and not TNF produced by
macrophages working to induce inflammation.
That you take these two resources as proof that TNF is
only ever created by adipocytes is evidence of your blind
devotion to your theory, and its dogma, as opposed to the
"search for truth" you've valued so highly in the past.
Hypocrite.
>You have never shown that it is *produced* by psoriasis or
>inflamation, because you cannot.
No, it's a *given* that TNF *produces* inflammation, such as in
psoriasis. Where there is inflammation, there are pro-
inflammatory cytokines. You can't get inflammation without
them.
>You speculated that this was the case and you are wrong !
No, I didn't speculate at all. I read the resources I've posted.
You have not, and are arguing about something which you
*admittedly* know very little. Hypocrite.
>Therefore psoriasis cannot produce IR , at least via TNF !
Since your premise is incorrect, your conclusion here is
invalid.
>You cannot see the wood from the trees. Ever ! Did you ever
>understand or qualify for anything ?!
Did you?
>The TNF, probably as a biological restraining
>factor, starts to induce resistance to the mass of insulin being produced
>in an attempt to stem the buildup of triglycerides being produced by the
>flood of glucose, by down regulating the PPAR expression.
Baloney. TNF causes insulin resistance in *all* humans, not just those
with thrifty genes. *Surgery* causes insulin resistance. TNF stops IRS-1
from doing its job, regardless of genetics, and regardless of its effects on
PPAR gamma.
Yes, it also has an effect on PPAR gamma, but you have yet to show
*how* PPAR gamma down-regulation induces insulin resistance. You
take that on faith just like so many other things.
>Through at
>least this and maybe some other mechanism inflamation is produced by the
>TNF, and probably other cytokines, probably also produced by this
>situation.
Look at all those 'probably's. Someone is taking a trip down
guesswork lane. Psoriasis is, according to the literature, associated
with a rise in *many* of the type-1 pro-inflammatory cytokines, and not
just TNF.
>The TNF fits like a glove into the Syndrome X explanation. It is as a
>result of glucose overload and consequent TG production and *not*
>produced from psoriasis or inflammation.
No, the TNF *produces* the inflammation that is a hallmark of
psoriasis. I've never claimed anything else. TNF is *mainly* created
by the immune system cells which are partly the cause of psoriasis.
To give *your* explanation of TNF a firmer footing, you should show
*where* in the body the inflammation due to adipocyte-created TNF is
located (if there is any). If it is *only* in the skin and joints, you *might*
be onto something.
>TNF looks like it contributes to
>or even causes, maybe alone maybe not, psoriasis, IR and inflamation.
Bravo. That's my case exactly. The immune system in psoriasis
creates a ton of TNF in order to get the inflammation going, and that
TNF causes insulin resistance, which in turn causes compensatory
hyperinsulinism, which, the last two together, cause the diseases of
IR.
What you don't seem to get is that in TNF-induced IR due to the
chronic inflammation of psoriasis, there is no *need* for adipocyte-
created TNF at all. So, where your theory, by necessity, tosses out
"10-30%" of psoriatics as being oddballs because they're not insulin
resistant, my theory could account for 100% of the IR found in
psoriasis.
Note also that my theory does not *exclude* thrifty genes as a
cause of IR. Why should it? A person with psoriasis *and*
thrifty genes should be even *more* cautious wrt diet, since they
are in a higher risk group than those people who only have psoriasis
or those people who only have thrifty genes, perhaps.
eve...@rocketmail.com
stran...@aol.com (DaveW) wrote:
Here is what you stated : psoriasis causes IR, because TNF is associated
with the inflamation of psoriasis (and any other inflamation) and TNF
causes IR, therefore psoriasis causes IR.
That is wrong ! The amount of TNF created is *only* dependant on the
amount of triglycerides (TG's) and not on the amount of inflamation or
psoriasis. TNF has a role in *causing* inflamation and IR. There is no
role for inflamation to create TG's, and therefore no role for
inflamation to create TNF. TG's are *only* created by converting glucose
to fat using insulin.
You have it backwards , as usual.
Steve
eve...@rocketmail.com
stran...@aol.com (DaveW>> wrote:
>
> What you don't seem to get is that in TNF-induced IR due to the
> chronic inflammation of psoriasis, there is no *need* for adipocyte-
> created TNF at all.
You must show me *one* reference where the amount of TNF is *explicitly
not* dependant on the amount of adipocyte cells (triglycerides) and I may
believe you. You have not because I don't believe it is possible based on
the references that I showed. Don't give me some "immune system" crap. I
want specifics, just like I gave you.
Steve.
eve...@rocketmail.com
TNF is produced as a result of oxidisation of LDL (a type of
fat(triglceride) significantly elevated and a marker in Syndrome X)
http://diss.kib.ki.se/abstract/970606jovi.html
Steve
Jerry J
>
> TNF is produced as a result of oxidisation of LDL (a type of
> fat(triglceride) significantly elevated and a marker in Syndrome X)
>
> http://diss.kib.ki.se/abstract/970606jovi.html
Gary, its not fair to just pick out words from the abstract and
rearrange them as you like. LDL is not the same as triglyceride. It
is the acronym for Low Density Lipoprotein. Triglyceride is often
referred to as VLDL, or very low density lipoprotein.
Did you even read this abstract? The author is showing that LDLs
which have accumulated on vessel walls and been modified by "local
oxidative processes" increase secretion of TNF by smooth muscle
cells and that TNF *leads to* increased levels of triglycerides by
inhibiting the enzyme that degrades trigs.
Thats pretty different than what you wrote above...
--
Cheer,
Jerry J
http://www.jhj.com/pbooks/
Jerry J
>
> Yes, you are correct. LDL's are not triglycerides, they are blood
> fats(cholesterol) and not adipose fat.
Wow, you need a medical dictionary. Here's a few definitions from my Dorland's:
"cholesterol - a pearly, fatlike steroid alcohol, C27-H45-OH"
"lipoprotein - a combination of a lipid and protein, posessing the
general properties of proteins. Practically all of the lipids of the
plasma are present as lipoprotein complexes.
HDL - a plasma lipoprotein containing high levels of protein, little
triglycerides, moderate levels of phospholipids, and relatively
little cholesterol.
LDL - a plasma lipoprotein containing a low percentage of
triglycerides, moderate levels of phospholipids, high levels of
cholesterol, and moderate levels of protein.
VLDL - a plasma lipoprotein containing high concentrations of
triglycerides, moderate concentrations of both phospholipids and
cholesterol, and little protein."
"adipose - the fat present in adipose tissue"
Adipose tissue is fat cells. Nothing to do with plasma (blood)
lipids.
I do not enjoy re-typing information from a dictionary but when you
make statements like that, I must.
--
Pbbbfffft,
Jerry J
http://www.jhj.com/pbooks/
eve...@rocketmail.com
j...@jhj.com wrote:
> eve...@rocketmail.com wrote:
> Did you even read this abstract? The author is showing that LDLs
> which have accumulated on vessel walls and been modified by "local
> oxidative processes" increase secretion of TNF by smooth muscle
> cells and that TNF *leads to* increased levels of triglycerides by
> inhibiting the enzyme that degrades trigs.
>
> Thats pretty different than what you wrote above...
Yes, you are correct. LDL's are not triglycerides, they are blood
fats(cholesterol) and not adipose fat. Very different. So the sequence
of events that I guessed now probably involve the additional step of
oxidized LDL's in elevating triglycerides via production of TNF. Since
elevated LDL's and depressed HDL's and small particle VLDL's, in
addition to IR etc are markers for Syndrome X, I would still have to say
, even more strongly now, that psoriasis is a disease of Syndrome X
rather than psoriasis causing all the markers for Syndrome X,
essentially as Dave says. If what Dave says is true it would certainly
stand the entire Syndrome X research on its head.
Steve.
DaveW
> Here is what you stated : psoriasis causes IR, because TNF is associated
> with the inflamation of psoriasis (and any other inflamation) and TNF
> causes IR, therefore psoriasis causes IR.
Substitute "can cause" for each of your "causes," and you've got it right,
even if grammatically odd.
> That is wrong ! The amount of TNF created is *only* dependant on the
> amount of triglycerides (TG's) and not on the amount of inflamation or
> psoriasis.
*NO*. You are wrong on the "only" you've stuck in there. You haven't
read one thing I've written. Were you born with those blinders on?
The sources you've cited claim that levels of TNF in *diabetics* are
dependent on amount of triglycerides. How many of those tested also
had a chronic inflammatory disease? How many had *psoriasis*? Were
the researchers *testing* for such correlations? How do you know?
It seems easy for you to assume you know everything about the production
of TNF from two resources, but there are thousands of *other* references
out there. An Alta Vista search returns over 13,000 Web pages referring to
TNF. It's obvious you have no clue about the full spectrum of TNF causes
and effects, yet you are arguing it. You are a hypocrite of the highest order.
> TNF has a role in *causing* inflamation and IR.
*Exactly*! Thank you for agreeing with that much.
> There is no role for inflamation to create TG's, and therefore no role
> for inflamation to create TNF.
Inflammation *doesn't* create TNF. Damn, I thought you understood
that, just one sentence ago. Silly me.
> TG's are *only* created by converting glucose to fat using insulin.
No. TGs are *also* created by converting FFAs. But so what?
> You have it backwards , as usual.
No, you've got your blinders on. You refuse to see the evidence I've
already set before you that TNF is created by cells *other than*
adipocytes. I'll give you some more, in a minute, just to see if I can
punch through the haze in front of your eyes.
> You must show me *one* reference where the amount of TNF is *explicitly
> not* dependant on the amount of adipocyte cells (triglycerides) and I may
> believe you.
This may be impossible due to your request. You are asking me to find a
reference which says, basically, "we found these TNF levels, which are
*not* correlated with adiposity." Who is going to write something like
that?
> You have not because I don't believe it is possible based on
> the references that I showed.
No, I just believe it may very well be an impossible request. Like if I
were to ask you to prove that severity of head colds is *not* correlated
with, say, hangnail incidence. Could you do that from Medline cites?
Also, the references you've cited do *not* state that TNF is *only* created
by adipocytes. They state that in *diabetics*, TNF levels are correlated
with adiposity. There *is* a cause-and-effect chain there, but that's *not*
the chain I'm talking about at all.
Hey, in that big article by Reaven, he doesn't mention TNF at all when
discussing obesity and IR. By your 'logic', wouldn't that be evidence that
there's no relationship between TNF and adipocytes at all? Doesn't that,
by your way of thinking, contradict those two cites of yours?
Not a single one of my footnotes on the connection between psoriasis and
TNF mentions adipocytes. Not one. None mention obesity, either. The
only safe assumption to make, therefore, is that those comparing psoriatics
to a healthy control population, weight distribution was about equal, and
so TNF levels should have been equal if only adipocytes make TNF.
I can, however, show you how wrong you are in your assumption that only
adipocytes create TNF. I added 34 more footnotes tonight, some of which
deal with this directly. Don't forget that these are all articles published in
peer-reviewed journals, so by your publicly-stated standards, they must all
be correct:
Footnote 43 says, in part,
"To evaluate the immunological function of peripheral blood monocytes
(PBMC) in psoriasis, we measured spontaneous production of the
inflammatory cytokines, TNF-alpha, IL-1beta and IL-6 from the PBMC of
psoriasis patients, by enzyme linked immunosorbent assay (ELISA)."
See? PBMCs create TNF, too.
48:
"There are several lines of evidence that changes in cytokine production
by keratinocytes and immunocompetent cells in the skin of the patients
(particularly of interleukin-6 and TGF-alpha) may play an important role
in the propagation of the inflammatory response in psoriasis."
So keratinocytes and "immunocompetent cells" also produce TNF.
49:
"...tumor necrosis factor-alpha was identified in 12 psoriatic lesions
as intense and diffuse expression by dermal dendrocytes (macrophages)
...and focally by keratinocytes and intraepidermal Langerhans cells..."
Again, keratinocytes, and now dermal dendrocytes and intraepidermal
Langerhans cells.
50:
"It is concluded that psoriatic monocytes spontaneously produce higher
than normal levels of TNF alpha..."
Monocytes, again.
51:
"Activated Langerhans cells may contribute to inflammation in the skin
by releasing TNF-alpha..."
Langerhans cells, again.
44 is pretty clear:
"TNF-alpha and IL-6 levels of involved skin blister fluids showed
significant correlations with the psoriasis area and severity index
scores in the patients, suggesting a direct relationship between
these cytokines and the clinical manifestations of the disease."
But go to http://members.aol.com/psorsite/docs/ir_risk.html and read for
yourself. Follow the links from footnotes 19, and 38 through 51,
inclusive. Go read Britannica's definition of TNF again. It doesn't
mention adipocytes at all.
> Don't give me some "immune system" crap.
Bwahahahahaha! Do you want proof that psoriasis is *characterized by*
an immune system gone nuts, too? Do you not believe it? All you've
gotta do is read some NPF literature (which you've hardly ever done).
Hey, since you believe that "since TZD helps psoriasis, then psoriasis
must be a disease caused by IR," then you should also believe that
"since immune-suppressing agents, such as Cyclosproin A, help
psoriasis, psoriasis must be a disease caused by the immune system."
How do you keep those two conflicting ideas in your head at the same
time? Zen training?
You've proven to me and a few others here that you know nothing of
TNF (except as it relates to adiposity in diabetes, of course), and now
very little of psoriasis, and even less of the immune system. You are a
hypocrite beyond belief for arguing this when you know so little.
The immune system aspect of this is not crap at all, it's very important,
since psoriasis is primarily an immune system disease.
> I want specifics, just like I gave you.
I won't give you specifics *just like* you gave me, because your specifics
don't have squat to do with Syndrome X in general, nor psoriasis in general.
You've taken a *very* specific set of two resources, and generalized them
to include the *entirety* of humanity. I shouldn't be surprised, since this
is your usual M.O., but I'll be damned if I'm going to follow your horrible
example.
Besides which, I'm still waiting on answers from you for other questions
about your theory. Why should I go into specifics when *you* haven't?
Hypocrite.