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The Marshall Protocol Study Site > PROF. MARSHALL'S PERSPECTIVE > Prof. Marshall's Perspective > Cathelicidin is Badly Deficient in Seriously ill Sarcoidosis Patients


Cathelicidin is Badly Deficient in Seriously ill Sarcoidosis Patients
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Prof Trevor Marshall
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 Posted: Thu Jul 5th, 2012 14:16

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Dan Culver's colleagues have a new paper out:

"Alveolar Macrophage Cathelicidin Deficiency in Severe Sarcoidosis"
(Barna BP, Culver DA, Kanchwala A, Singh RJ, Huizar I, Abraham S, Malur A, Marshall I, Kavuru MS, Thomassen MJ)

http://www.ncbi.nlm.nih.gov/pubmed/22759465

Of particular interest to me is that they found that TNF-alpha seems to act via SRC3 (I call SRC3 as DIST205 in my presentations), the co-activator which binds the VDR and RXR receptors together so they can transcribe cathelicidin. They conclude:

"These findings suggest that TNF╬▒-mediated repression of SRC3 contributes to alveolar macrophage cathelicidin deficiency in severe sarcoidosis despite healthy vitD3 levels. [they mean 1,25-D levels] Deficiency of cathelicidin, a multifunctional regulator of immune cells and proinflammatory cytokines, may impede resolution of inflammation in the lungs of patients with severe sarcoidosis"

So VDR gene transcription is multifactorial - not just via the 1,25-D (Calcitriol pathway).
Just what we have been saying all along -- it is nice to have some more solid data backing up our pathogenesis...

..Trevor..

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 Posted: Fri Jul 6th, 2012 13:34

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This is exciting research.

Will anyone notify the authors of our cohort's progress and the ARE's published papers backing up the findings?

Sherry



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Prof Trevor Marshall
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 Posted: Fri Jul 6th, 2012 14:21

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Sherry, I have emailed Dan Culver with a copy of our own recent paper, and will try to keep in better communication with him as we move forward, as it is clear he is no longer in lockstep with the other sarcoid pulmos...
 

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 Posted: Fri Jul 6th, 2012 14:35

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so tnf alpha blocks vdr activation? Does it meam that coffee, which also raises tnf-alpha, will block innate immunity this way?



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Prof Trevor Marshall
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 Posted: Fri Jul 6th, 2012 16:00

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Well, coffee probably changes hundreds of other pathways too, but, from this study,  it would seem that anything increasing TNF-alpha would interfere with gene expression by the VDR.
 

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 Posted: Fri Jul 6th, 2012 16:18

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Dang!  So in addition to giving up D foods, nightshades, and wheat (all of which have really helped, by the way), I now have to give up that morning cup of java as well? :shock:

Pass the lettuce, please! 



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Prof Trevor Marshall
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 Posted: Fri Jul 6th, 2012 16:38

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You could try Hot Chocolate. Nobody has studied that yet :) :)
 

wrotek
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 Posted: Fri Jul 6th, 2012 21:06

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lol frozen water aint bad dish, especially with those heats. I cant imagine how it must be in sunny California. In Poland we have 33 celcius now. PaisleyKilt, i have always dreamed of composing no-inflammation producing diet. From what i can see, coffee, nightshade and wheat ellimination is a good start. Although i love how those things taste like too. But inflammation is what gives us physical pain in life, also mental like depression.



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 Posted: Fri Jul 6th, 2012 21:23

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wrotek wrote: I cant imagine how it must be in sunny California. In Poland we have 33 celcius now
Well, it rose to 30 degrees inside this afternoon, so I opened the windows tonight, switched on the whole-of-house fan in the hallway, and cool air is caressing me at the moment :) Thermometer says 22 C.

I am sure there are hotter spots elsewhere in California, but we are in a corner of Thousand Oaks which gets the sea breeze up the Santa Rosa Rd (and pass) and very few nights are unbearable here :) :)
 
So I am still working at full pace :) :)
 

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 Posted: Sat Jul 7th, 2012 06:05

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That's what A/C is for, although the sea breezes sound lovely! I miss the ocean.

Deb



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 Posted: Sat Jul 7th, 2012 07:44

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Paisleykilt wrote:
Dang! So in addition to giving up D foods, nightshades, and wheat (all of which have really helped, by the way), I now have to give up that morning cup of java as well? :shock:

Pass the lettuce, please!
what did nightshade and wheat ellimination do for you ?



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wrotek
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 Posted: Sat Jul 7th, 2012 08:29

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dr Marshall. One Coffee a day increases tnf alpha by 28% ,is this much to affect vdr significantly?



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 Posted: Sat Jul 7th, 2012 09:49

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wrotek wrote: what did nightshade and wheat ellimination do for you ?
Hi wrotek,

Eliminating nightshades seemed to reduce joint pain.

Eliminating wheat seems to be reducing stomach/GI problems along with feeling less sluggish/fatigued overall. 

I hope I don't have to completely banish these things from my diet forever, but while I'm in recovery mode (likely the next several years), it's probably wisest to avoid them altogether.  At a recent family event, I had some processed foods with goodness-knows-what in them and felt awful for most of the week thereafter.

I lowered my coffee intake as of this morning. Will do one week at half a cup or so, then try to quit.   Sigh.  :?

Perhaps we should move this over to another thread re diet and what helps/doesn't help inflammation?



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wrotek
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 Posted: Sat Jul 7th, 2012 13:57

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Paisleykilt, does not tea stimulate U enough ? I have always experienced the smell of coffee as terpentine or even worse...purines, like urine :) (ill be honest) with these worst kinds- soluble coffees. That is why i've always had an espresso fast down the drain, well pressed with enough pressure. Then it tasted well enough.

But lets go back to tnf-alpha, here is a paper i found. I finally learned to search if any study was posted before on the board, not to duplicate them.

http://www.ncbi.nlm.nih.gov/pubmed/8213262

Tumor necrosis factor alpha decreases 1,25-dihydroxyvitamin D3 receptors in osteoblastic ROS 17/2.8 cells.


Abstract
Bone remodeling is a complex process regulated by systemic hormones, local cytokines, and growth factors. One cytokine, tumor necrosis factor alpha (TNF-alpha), is known to have potent inhibitory effects on osteoblast matrix protein production and to stimulate osteoclast recruitment. We have previously shown that TNF-alpha inhibits 1,25-(OH)2D3-stimulated synthesis of bone gla protein (BGP), an abundant and osteoblast-specific matrix constituent. We hypothesized that the mechanism of TNF-alpha action included inhibition of intracellular 1,25-(OH)2D3 receptor (VDR) number or function. To test this, the osteoblastic cell line ROS 17/2.8 was cultured in the presence or absence of TNF-alpha (100 ng/ml), and binding of [3H]1,25-(OH)2D3 to 0.3 M KCl extracts of cytosol was measured by equilibrium assay. Specific [3H]1,25-(OH)2D3 binding decreased 70%, 25 h after addition of TNF-alpha. The decrease in [3H]1,25-(OH)2D3 binding was seen by 18 h, was sustained throughout the 72 h culture period, and was greater in low-density cultures. Scatchard analysis confirmed that TNF-alpha (100 ng/ml for 24 h) caused a decrease in the number of binding sites without change in VDR affinity. Northern analysis with a VDR riboprobe revealed that the decrease in VDR occurred without a change in the 4.4 kb steady-state VDR mRNA [VDR/cyclophilin mRNA signal ratio: control, 2.25; TNF-alpha, 2.24 (24 h), 2.17 (40 h), n = 2 flasks/time point]. These results suggest that TNF-alpha action on osteoblastic cells includes an inhibitory effect on VDR number at a point distal to the synthesis of VDR mRNA.



Perhaps this can support Dr Marshall title post.

Last edited on Sat Jul 7th, 2012 14:12 by wrotek



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 Posted: Sat Jul 7th, 2012 14:16

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Here is another paper.
http://www.ncbi.nlm.nih.gov/pubmed?term=15211579

Integration of the NfkappaB p65 subunit into the vitamin D receptor transcriptional complex: identification of p65 domains that inhibit 1,25-dihydroxyvitamin D3-stimulated transcription.



Abstract
Resistance to the action of vitamin D (D) occurs in response to tumor necrosis factor-alpha (TNF-alpha), an effect mediated by nuclear factor kappa B (NfkappaB). To determine the mechanism of NfkappaB inhibition of D-stimulated transcription, chromatin immunoprecipitation assays (CHIP) were done in osteoblastic ROS 17/2.8 cells that had been treated with TNF-alpha or transfected with the p65 subunit of NfkappaB. These treatments caused stable incorporation of p65 into the transcription complex bound to the vitamin D response element (VDRE) of the osteocalcin promoter. Deletion analysis of p65 functional domains revealed that the p65 N-terminus and a midmolecular region were both required for the inhibitory action of p65. Pull-down assays were done using an immobilized glutathione S-transferase (GST)-VDR fusion protein to study the effect of p65 on VDR binding to steroid coactivator-1 (SRC-1), a major D-dependent coactivator. p65 inhibited VDR-SRC-1 binding in a dose-dependent manner. Mutations of p65 that abrogated the inhibitory effect on D-stimulated transcription also failed to inhibit VDR-SRC-1 binding. The inhibitory effect of p65 on VDR transactivation was not due to recruitment of a histone deacetylase (HDAC), since inhibition was not relieved by the HDAC inhibitors sodium butyrate or trichostatin A. Overexpression of SRC-1 or the general coactivators, Creb binding protein or SRC-3, also failed to relieve p65 inhibition of transcription. In addition, Chip assays revealed that TNF-alpha treatment prevented D recruitment of SRC-1 to the transcription complex. These results show that TNF-alpha inhibition of vitamin D-action includes stable integration of p65 in the VDR transcription complex. Once anchored to proteins within the complex, p65 disrupts VDR binding to SRC-1, thus decreasing the efficiency of D-stimulated gene transcription.

Copyright 2004 Wiley-Liss, Inc.

PMID: 15211579 [PubMed - indexed for MEDLINE]

Last edited on Sat Jul 7th, 2012 14:26 by wrotek



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Prof Trevor Marshall
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 Posted: Sat Jul 7th, 2012 14:38

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Wrotek, there is great molecular complexity in these two papers. Can you get your mind around it? In any case it is still an acknowledged subset of the relevant Interactome space.

I am asking because if I get involved in trying to explain exactly what these abstracts are saying, I will have to go back over a lot of basic, as well as advanced molecular biology, and I am not sure whether I might confuse you even more.

Maybe you can give a quick precis of what you think they say, and I can then focus on the parts which most need clarification.

..Trevor..

wrotek
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 Posted: Sat Jul 7th, 2012 15:07

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Nope i dont think i can do that Dr Marshall, but i appreciate Your faith in me. It is all over my head.

All i can understand is the simple interactions.

Tnf alpha disturbs VDR.

I am not qualified.

But I can Always assist You to find similar papers.

Well ok i might think i know something, but that was incorrect many times . :)

For example this

Scatchard analysis confirmed that TNF-alpha (100 ng/ml for 24 h) caused a decrease in the number of binding sites without change in VDR affinity


decrease in binding sites ?

Last edited on Sat Jul 7th, 2012 15:44 by wrotek



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 Posted: Sat Jul 7th, 2012 15:55

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I am trying to bend my Lyme fogged mind around all this, but in VERY simple terms are the papers saying that if I drink coffee I am actually helping knock out my innate immune system?

If that's wrong, please correct me, but I just had a bit of an epiphany: I didn't start drinking coffee until about age 35  - and that is when I started to have some serious health issues. 

Coincidence or Coffee uptake?!?  :shock:



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"Life is a whim of several billion cells to be you for a while." Groucho Marx.
MP start May'11 (2 breaks: one in December '15 and one Jan-Mar '18) | Lyme Disease '93, CFS/ME '10 | muscle/joint pain, severe fatigue, myriad neurological symptoms
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 Posted: Sat Jul 7th, 2012 16:01

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Mornings won't be very pleasant if I have to quit my 1 cup of coffee a day.



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I just know that something good is going to happen
And I don't know when - Kate Bush
Aplastic anemia Apr/10, PRCA Jan/09, Agranulocytosis 1991
25D = 25 1,25D = 58 Aug 18/09|25D<4.8 Mar/10|10.8 Nov/12
Sep '09 q8h Nov '09 q6h
Paisleykilt
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 Posted: Sat Jul 7th, 2012 16:20

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wrotek wrote: Paisleykilt, does not tea stimulate U enough ? I have always experienced the smell of coffee as terpentine or even worse...purines, like urine :) (ill be honest) with these worst kinds- soluble coffees. That is why i've always had an espresso fast down the drain, well pressed with enough pressure. Then it tasted well enough.


 

Being a Brit, I was raised on tea, so I never got into the habit of drinking coffee until I worked at a place where the breaks were too short to make tea. The coffee pot was always on, so one day I caved and started drinking the stuff even though I did not like the taste. The aroma was okay. 

However, I never became addicted to anything as quickly as I became addicted to coffee!  I don't smoke and drink alcohol only moderately, but coffee?  Oh man, I needed to go to Coffaholics Anonymous!  :(  It took a long time to get down to one cup a day, which I thought was okay on the MP....



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"Life is a whim of several billion cells to be you for a while." Groucho Marx.
MP start May'11 (2 breaks: one in December '15 and one Jan-Mar '18) | Lyme Disease '93, CFS/ME '10 | muscle/joint pain, severe fatigue, myriad neurological symptoms

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