doi:10.1016/S0306-4530(97)00076-0

Effect of nicotine on the immune system: Possible regulation of immune
responses by central and peripheral mechanisms

Nicotine (NT) treatment impairs T-cell receptor (TCR)-mediated
signaling, leading to the arrest of T cells in the G1 phase of the
cell cycle and inhibition of the antibody plaque-forming cell (AFC)
response to sheep red blood cells (SRBC). This paper summarizes some
of the previous findings related to cigarette smoke/NT and the immune
response, and presents preliminary evidence suggesting that mice
chronically treated with NT (0.5 mg/day/kg body weight) have a
depressed inflammatory response in the turpentine-induced abscess
model of inflammation. This ability of nicotine to attenuate an
inflammatory response may also be the cause of reduced mortality of
chronically nicotine-treated mice from acute influenza A pneumonitis.
Moreover, in LEW rats, decreased anti-SRBC AFC responses were also
observed after intracerebroventricular (ICV) administration of
relatively small concentrations of NT (28 μg/day/kg body weight)
which, when given peripherally, did not affect the AFC response. In
vitro the addition of NT to T cells increased protein tyrosine kinase
(PTK) activity and intracellular Ca2+ concentration [Ca2+]i. These
results support the hypothesis that NT alters immune responses by
directly interacting with T cells, as well as indirectly through brain-
immune interactions.

Adv Exp Med Biol. 1998;437:279-89.

Nicotine-induced modulation of T Cell function. Implications for
inflammation and infection.

Sopori ML, Kozak W, Savage SM, Geng Y, Kluger MJ.
Pathophysiology Division, Lovelace Respiratory Research Institute,
Albuquerque, New Mexico 87108, USA.

Tobacco smoking may predispose humans to respiratory disease, and may
be a compounding risk factor in HIV infection and progression to AIDS.
We have demonstrated that chronic exposure of mice and rats to
cigarette smoke or nicotine inhibits T cell responsiveness, which may
account for the decreased antibody response to T-dependent antigens
seen in these animals. This inhibition may result from aberrant
antigen-mediated signaling and depletion of IP3-sensitive Ca2+ stores
in nicotine-treated animals. Moreover, nicotine appears to moderate
the inflammation associated with turpentine-induced sterile abscess
and influenza infection. These anti-inflammatory properties of
nicotine may account for longer survival of nicotine-treated than
control mice lethally infected with influenza virus. However, because
inflammation is required for clearance of many pathogens, nicotine-
treated mice exhibit significantly higher titers of influenza virus
following infection. These results offer an explanation for the higher
susceptibility to some infectious diseases, but greater resistance to
some inflammatory diseases among human smokers.
PMID: 9666281

That's merely a tip of the iceberg for this ancient medicinal plant.
Here are few beneficial effects of tobacco smoke (most not due to
nicotine):

1. Upregulates glutathione (by 80%), catalase and SOD (by 100%).

2. Selective MAO B inhibition (by 40%), much safer and more harmonious
with overall biochemistry than via selegiline. Smokers in their 50s
have MAO B of non-smokers in their 20s.

3. Dopamine (throughout the body, including brain), acetylcholine and
norepinephrine are also stimulated directly (protective & therapeutic
for ADD, Tourette, anxiety, depression, schizophrenia).

4. Upregulates pregnenolone, DHEA and testosterone and slows down
their decline with age (protective against endometrial cancer &
endometriosis).

5. Upregulates telomerase and suppresses apoptosis (protects against
Alzheimer's, Parkinson's, also via 1,2 & 3; e.g. resulting in tenfold
lowered rates for early onset Alzheimer's, twelvefold for early
Parkinson's; protective in strokes & spinal injuries).

6. Upregulates vascular growth factor (via nicotine CO, NO).

7. Provides CoQ10 (which is even manufactured from tobacco) & niacin
directly into arterial bloodstream.

8. Upregulates neutrophiles (by 20%)

9. Reduces appetite and increase basal metabolism.

10. Suppresses amyloidosis throughout tissues, not just brain

12. Improves insulin sensitivity, protects against & alleviates
diabetes.

13. Anti-inflammatory effects at multiple levels, from T-cells through
CNS vagus/'cholinergic anti-inflammatory' pathway (therapeutic &
protective against asthma, allergies, ulcerative colitis, IBD, colon
cancer, apthous ulcers, arthritis, pre-eclampsia, endotoxemia,
polymicrobial sepsis...)

14. Downregulates IGF-1

15. Downregulates NF-kB

16. Upregulates bFGF (basic fibroblast growth factor) and MMPs
(expression of several matrix metalloproteinases)

17. Increases BDNF (brain-derived neurotrophic factor) expression

18. Reduces TNF-alpha and increases adiponectin (adipocyte effects)

... and so on.

The net effect is that smoking animals (such as mice, rats, hamsters,
dogs,... even those smoking at 5+ packs/day equivalents) live about
20% longer, stay 10-15% thinner and sharper throughout. Smokers are
over-represented among supercentenarians and, among others the oldest
man and the oldest women ever were smokers (the only two humans who
lived over 120). The current oldest man is also a lifelong smoker. The
oldest marathon runner (completed London marathon at age 101) even
smoked few cigarettes during the marathon.

After 6+ decades of massive efforts to demonstrate experimentally any
harm at all from inhalation of tobacco smoke, pharma sponsored
antismoking researchers still don't know how to shorten the lifespans
of test animals via inhalation of tobacco smoke, short of gross smoke
asphixiation (you could cause same kind of overdose harm with plain
water and it's easier to overdose on water than on tobacco smoke).

The entire antismoking "science" (sponsored and publicised mainly by
Big Pharma, which battles and suppresses as much as it can all other
natural & folk medicines as well) rests entirely on blind statistical
correlations on non-randomized (self-selected subjects) samples of
smoking with 'smoking related diseases'. Such non-randomized
correlations are equally consistent with beneficial and causal role of
tobacco smoke in those diseases. This is no different than observing
that people using statins or blood pressure medications will have more
heart attacks than those not using them. Or that people wearing
sunglasses will have more sunburns and skin cancers thn those not
wearing them. Sunglasses are merely a statistical marker for sun
exposure. Similarly, use of tobacco smoke is a proxy for any exposure
or biochemical/genetic malfunction for which the enumerated effects
are protective and therapeutic.

For example, the upregulation of the main internal antixoidants &
detox enzymes (1), implies that tobacco smoking will protect against
and alleviate the harmful effects of most industrial and environmental
toxins, hence people suffering such toxic exposures, or those
especially sensitive to them, would perceive tangible benefits from
smoking due to doubled detox rates (this has been experimentally
verified animal experiments and observed in human studies), thus they
would smoke more than general population, resulting thus in
statistical correlations with diseases (e.g. lung cancer, copd) caused
by the very same toxins against which tobacco smoke is protective.

See references & further discussions here:

Site: Smoking is good for you (a friend who liked ideas)
http://www.wispofsmoke.net/goodforyou.html

Some online books & papers for the above page
http://www.wispofsmoke.net/goodreads.html

The Scientific Scandal of Antismoking
http://members.iinet.com.au/~ray/TSSOASb.html

Discussion 1 (imminst/nootropic forum)
http://www.imminst.org/forum/index.php?s=afe84afcd59328b5da1c047f937d72a0&showto
pic=15125&view=findpost&p=166023

Discussion 2 (imminst/nootropic forum)
http://www.imminst.org/forum/index.php?showtopic=24284&st=0&p=263376&#entry263376

Discussion in nootropic section of m&m forum
http://www.mindandmuscle.net/forum/index.php?showtopic=35287&st=30&p=508486&#ent
ry508486

Harm from quitting
http://forum.ryorevolution.com/viewtopic.php?p=14089#p14089

Refs & discussion of longevity experiments & facts
http://www.freerepublic.com/focus/news/2262644/posts?page=#13

Amyloidosis effects
http://scholar.google.com/scholar?num=50&hl=en&lr=&safe=off&q=amyloidosis+%28nic
otine+OR+tobacco%29&btnG=Search

Neurotrophic effects
http://scholar.google.com/scholar?hl=en&q=neurotrophic+effects+%28nicotine+OR+to
bacco%29&btnG=Search

Neuroprotective effects
http://scholar.google.com/scholar?hl=en&q=neuroprotective+effects+%28nicotine+OR
+tobacco%29&btnG=Search

Petr Skrabanek (books in pdf format)
* Follies and Fallacies in Medicine
http://www.curezone.com/upload/pdf/books/Follies-and-Fallacies-in-Medicine-1up.pdf
* Death of Humane Medicine
http://www.curezone.com/upload/pdf/books/Death-of-Humane-Medicine.pdf
* False Premises False Promises
http://www.curezone.com/upload/pdf/books/False-Premises-False-Promises.pdf

Thanks Taka,

I read about this linkage years ago and it has always fascinated me. Central
Ach modulates systemic inflammation, at a big guess I imagine because it
energises the hippocampal region, a possible downstream effect of this being
modulation of the PVN. BIG guess. Ach is known to boost nerve growth factor
production, and coffee consumption also provides an Ach boost. Good Ach
levels are vital for memory. Ach is the first neurotransmitter that takes a
plummet in Alz and some other neurodegenerative disorders. Drugs for Alz
typically target Ache, an enzyme that breaks down Ach. There, is, however,
an interesting alternative:

Mol. Pharmaceutics, 3 (6), 773 -777, 2006. 10.1021/mp060066m
S1543-8384(06)00066-9

Web Release Date: August 9, 2006

Copyright © 2006 American Chemical Society

A Molecular Link between the Active Component of Marijuana and Alzheimer's
Disease Pathology

Lisa M. Eubanks, Claude J. Rogers, Albert E. Beuscher IV, George F. Koob,
Arthur J. Olson, Tobin J. Dickerson, and Kim D. Janda*

Departments of Chemistry, Immunology, and Molecular Biology, Molecular and
Integrated Neurosciences Department, The Skaggs Institute for Chemical
Biology, and Worm Institute for Research and Medicine, The Scripps Research
Institute, 10550 North Torrey Pines Road, La Jolla, California 92037

Received June 11, 2006

Abstract:

Alzheimer's disease is the leading cause of dementia among the elderly, and
with the ever-increasing size of this population, cases of Alzheimer's
disease are expected to triple over the next 50 years. Consequently, the
development of treatments that slow or halt the disease progression have
become imperative to both improve the quality of life for patients and
reduce the health care costs attributable to Alzheimer's disease. Here, we
demonstrate that the active component of marijuana, 9-tetrahydrocannabinol
(THC), competitively inhibits the enzyme acetylcholinesterase (AChE) as well
as prevents AChE-induced amyloid -peptide (A) aggregation, the key
pathological marker of Alzheimer's disease. Computational modeling of the
THC-AChE interaction revealed that THC binds in the peripheral anionic site
of AChE, the critical region involved in amyloidgenesis. Compared to
currently approved drugs prescribed for the treatment of Alzheimer's
disease, THC is a considerably superior inhibitor of A aggregation, and this
study provides a previously unrecognized molecular mechanism through which
cannabinoid molecules may directly impact the progression of this
debilitating disease.

Keywords: Cannabinoids; Alzheimer's disease; acetylcholinesterase

Scientific American; Jun2006, Vol. 294 Issue 6, p24-24, 1p, 1 color

HOW NICOTINE STOPS INFLAMMATION COULD LEAD TO NEW DRUGS

Body Blazes, Lisa Melton

* Nicotine has undergone * an image overhaul, at least biomedically.
In
the past few years researchers have found that the substance can
alleviate symptoms of ailments such as Alzheimer's disease and
ulcerative colitis. Just how nicotine battles these foes, however, has
remained unclear. Now, by studying sepsis, Luis Ulloa of North Shore
University Hospital in Manhasset, N.Y., has evidence elucidating
nicotine's biochemical pathways that could lead to more potent
anti-inflammatory drugs.

Sepsis, the most lethal of inflammatory conditions, is a bacterial
invasion of the bloodstream. The third leading cause of death in the
developed world, it accounts for nearly 10 percent of overall deaths
in
the U.S. every year. Infection causes part of the damage, but what
makes
patients critically ill is their own fiercely aggressive immune
response. Macrophages churn out huge quantities of proinflammatory
cytokines. This exaggerated immune response leads to tissue damage,
and
eventually the patient dies of cardiovascular dysfunction and
multiorgan
failure.

Ulloa and his collaborators have found something remarkable: nicotine
can shut down this overshooting inflammatory response, to the point of
reversing sepsis in mice. As far as anti-inflammatory treatments go,
this is powerful stuff. "Nicotine taps into the body's own potent
anti-inflammatory mechanisms," Ulloa explained in February at a
Novartis
Foundation meeting in London. "That is the beauty of our approach. By
using nicotine, we are copying physiological mechanisms that have been
selected by evolution to modulate the immune system."

Specifically, nicotine mimics acetylcholine, the Cinderella of
neurotransmitters. Largely ignored over the years, acetylcholine has
been catapulted into a starring role, linking the nervous and the
immune
systems. Through acetylcholine the nervous system controls the
inflammatory fires that constantly crop up in our bodies. Receptors
for
acetylcholine reside not only on nerve cell endings but also on immune
cells. Nicotine binds and activates these receptors, allowing cross
talk
between the brain and immune system.

"This is something quite phenomenal," comments Wouter de Jonge of the
Academic Medical Center Amsterdam, who studies how macrophages respond
to acetylcholine. "Smokers suffering from ulcerative colitis seemed to
benefit from their habit, so there were hints that nicotine could
ameliorate inflammatory diseases, but nobody could get a handle on
it,"
he notes.

Now Ulloa's group may have provided an explanation for the positive
effects that nicotine has on illnesses as diverse as schizophrenia,
Alzheimer's, Parkinson's disease, Tourette's syndrome and ulcerative
colitis. In laboratory experiments, Ulloa demonstrated that nicotine
latches onto the nicotinic receptors on macrophages and stops them
from
spewing out inflammatory cytokines. This clampdown is brutally
effective. The researchers also identified the specific receptor
subtype, the alpha-7 acetylcholine receptor, that nicotine binds in
macrophages to stop cytokine production.

But as a drug, nicotine is fraught with toxicity issues. Apart from
its
addictive nature, it can lead to cardiovascular problems and
contribute
to cancer. "No one is looking to use nicotine to treat inflammation,"
Ulloa says. "We want to design specific compounds that will target
this
receptor to take advantage of nicotine's anti-inflammatory effects
while
eluding its collateral toxicity."

"This is one of the great stories in immunology in the past few years—
no
question about it," remarks Mitchell Fink, an expert in critical care
medicine at the University of Pittsburgh. A selective nicotinelike
compound may be a promising therapy not only for sepsis but for a
whole
slew of chronic conditions, including heart disease, cancer and
diabetes. The task at hand is to find the best surrogate for nicotine.
Ulloa's petri dishes are the ones to watch.

A NICK OF NICOTINE

As a potent anti-inflammatory, nicotine can damp down a dangerous
immune
response. But it is too risky as a treatment. Fortunately, substitutes
may exist. Pharmaceutical firms have developed nicotinelike drugs,
such
as GTS-21, that were designed to stimulate the alpha-7 acetylcholine
receptors in the brains of patients with Alzheimer's disease. But the
clinical trials failed to show a clear benefit, and the drugs were
dropped. The compounds may have been unable to cross the blood-brain
barrier—which would actually be a plus for an anti-inflammatory,
because
then it could target the periphery and avoid the brain. Researchers
have
begun testing such substitutes to combat inflammation.