J. Biol. Chem., Vol. 278, Issue 40, 38829-38839, October 3, 2003

Cellular Cholesterol Depletion Triggers Shedding of the Human Interleukin-6 Receptor by ADAM10 and ADAM17 (TACE)^*,

</NOBR><NOBR>Vance Matthews</NOBR>, <NOBR>Björn Schuster</NOBR>, <NOBR>Stefan Schütze </NOBR>, <NOBR>Ingo Bussmeyer</NOBR>, <NOBR>Andreas Ludwig</NOBR>, <NOBR>Christian Hundhausen</NOBR>, <NOBR>Thorsten Sadowski</NOBR>, <NOBR>Paul Saftig</NOBR>, <NOBR>Dieter Hartmann </NOBR>, <NOBR>Karl-Josef Kallen ¶</NOBR> and <NOBR>Stefan Rose-John ¶ ||</NOBR>

Interleukin-6 (IL-6) activates cells by binding to the membrane-bound IL-6 receptor (IL-6R) and subsequent formation of a glycoprotein 130 homodimer. Cells that express glycoprotein 130, but not the IL-6R, can be activated by IL-6 and the soluble IL-6R which is generated by shedding from the cell surface or by alternative splicing. Here we show that cholesterol depletion of cells with methyl--cyclodextrin increases IL-6R shedding independent of protein kinase C activation and thus differs from phorbol ester-induced shedding. Contrary to cholesterol depletion, cholesterol enrichment did not increase IL-6R shedding. Shedding of the IL-6R because of cholesterol depletion is highly dependent on the metalloproteinase ADAM17 (tumor necrosis factor--converting enzyme), and the related ADAM10, which is identified here for the first time as an enzyme involved in constitutive and induced shedding of the human IL-6R. When combined with protein kinase C inhibition by staurosporine or rottlerin, breakdown of plasma membrane sphingomyelin or enrichment of the plasma membrane with ceramide also increased IL-6R shedding. The effect of cholesterol depletion was confirmed in human THP-1 and Hep3B cells and in primary human peripheral blood monocytes, which naturally express the IL-6R. For decades, high cholesterol levels have been considered harmful. This study indicates that low cholesterol levels may play a role in shedding of the membrane-bound IL-6R and thereby in the immunopathogenesis of human diseases.

^{On the internet:  http://www.jbc.org/cgi/content/abstract/278/40/38829}

^{This is important because, as these and other researchers point out, IL-6 is generally "bad news," for example:}

^QUOTE: 

IL-6 activates and enhances HHV-8 and HIV replication, Song and coauthors found.

The researchers used a BCBL tumor cell line to examine the effect of IL-6 on HHV-8 activity. Exposing these cells to IL-6 triggered the expression of viral genes needed for replication, they reported.

The effects of IL-6 on HIV replication, noted in previous studies, were also investigated by Song and coauthors. They confirmed that an HHV-8-encoded cytokine homologue stimulated HIV replication in chronically infected cells, and enhanced human IL-6 secretion by T-lymphoblastoid cells, according to the report.

These effects appeared to be mediated by the signaling molecule gp130 (Human interleukin-6 induces human herpesvirus-8 replication in a body cavity-based lymphoma cell line. J Med Virol 2002 Nov;68(3):404-11.

"These data suggest the possible existence of interaction between HIV and HHV-8 via IL-6," Song and colleagues concluded, "and that the blockade of IL-6 signal by anti-IL-6R antibody or anti-gp130 antibody can constitute a strategy to treat HIV/HHV-8 dually infected patients."

The corresponding author for this report is Norihiro Nishimoto, Department of Medical Science I, School of Health and Sport Sciences, Osaka University, 2-1 Yamada-oka, Suita-city, Osaka, 565-0871, Japan. E-mail: [email protected].

Key points reported in this study include:

• Interleukin (IL)-6 may play a key role in the development of several AIDS-related malignancies, including Kaposi sarcoma (KS)

• IL-6 activates and enhances human herpesvirus-8 (HHV-8) replication, the causative agent of KS and other AIDS-associated cancers

• HIV replication is also augmented by IL-6.   UNQUOTE.

^{Source:  http://www.aegis.com/pubs/aidswkly/2002/AW021202.html}

As Anthony Fauci himself has said:  "...So what is it about the human body, the host, that helps drive virus replication, and what is it that tries to block virus replication? And because of our work and work from other labs on various cytokines, like TNF-α and IL-6 and IL-1 beta, as well as the discovery the previous year of certain chemokines to suppress HIV replication, it looked like there was this delicate balance between stimulatory and inhibitory effects of host factors, particularly endogenous cytokines, on HIV replication. It was not just the virus operating in a vacuum. There was an important and complicated interaction with these host factors..."

Source: http://www.esi-topics.com/hiv-aids/interviews/AnthonyFauci.html

Where I differ with some of these kinds of "experts" is in the notion that a "germ" is the cause.  Instead, interpretation of the evidence as whole (that means including nutritional studies, molecular-level studies not supposedly directly related to "infectious disease," etc.) leads me to believe that it is much more likely that "germs" are just microscopic vultures, taking advantage of conditions that allow them to reproduce faster.  I am much more concerned about low cholesterol levels and oxidized cholesterol, whereas "experts" like Fauci think that the "germs" (assuming they exist, which is unlikely in the case of "HIV," which appears to be effect rather than cause) more or less will affect healthy, adult humans equally.  The "HIV/AIDS" idea is the worst, because healthy people are told that a "germ" will kill them within a dozen or so years, and that is if they endure highly toxic "medicines."  I don't see any evidence whatsoever that any "virus" could do this to a person, let alone a few "retroviral" particles that are just effects of cellular-level stress.  However, a person with low cholesterol and perhaps other unhealthy characteristics may indeed face a number of health crises (as I did).  If such a person is then given highly toxic "medicines," it is no wonder that they only live several more years.  In the wrong place and in a certain amount, a "germ" can basically speed up the damage (which occurs due to a dangerous "inflammatory" response) that one can get from low cholesterol over a longer period of time, but one would become very ill very quickly - it would not take several years to see severe symptoms.