enter for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02144; Abstract
IL-10-deficient mice infected with the relapsing fever bacterium Borrelia turicatae rapidly succumb to a brain hemorrhage if they are unable to clear peak bacteremia.
In this study, we investigated the protective role of IL-10 during relapsing-remitting bacteremia and explored the molecular events involved in the protection of brain endothelium by IL-10.
Brain endothelial injury was measured with cytotoxicity and diverse apoptotic assays, whereas the signaling pathway analysis was done by quantitative PCR array.
The results showed that severe endothelial cell injury leading to hemorrhage in the brain and other organs occurred in IL-10-deficient mice during relapsing-remitting infection.
Human brain microvascular endothelial cells (HBMEC) produced abundant proinflammatory mediators upon exposure to whole bacteria
or purified bacterial lipoprotein
but did not produce any detectable IL-10.
Whole bacteria and purified outer membrane lipoprotein rapidly killed HBMEC by apoptosis in a time- and concentration-dependent manner.
Exogenous IL-10 protected HBMEC from apoptosis.
HBMEC apoptosis during exposure to a low number of bacteria was associated with downregulation of TNF and TNFAIP3 and upregulation of BAX.
In contrast, HBMEC apoptosis during exposure to high concentrations of purified outer membrane lipoprotein was associated with marked upregulation of FAS, FAS ligand,
and the adaptor molecules RIPK1 and CFLAR. Exogenous IL-10 reversed all the apoptotic signaling changes induced by whole bacteria or its purified lipoprotein.
The results indicate that prominent brain endothelial cell apoptosis occurs during relapsing-remitting bacteremia in the absence of IL-10 and point to a prominent role for bacterial lipoprotein-mediated activation of FAS and caspase-3 in this process ------- This is a lot of info. and show the truth too....
-------------------- Suspected Lyme 07 Test neg One band migrating in IgG region unable to identify.Igenex Jan.09IFA titer 1:40 IND IgM neg pos 31 +++ 34 IND 39 IND 41 IND 83-93 + DX:Neuroborreliosis Posts: 5850 | From Kentucky | Registered: Dec 2008
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nefferdun
Frequent Contributor (1K+ posts)
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posted
What is IL-10?
-------------------- old joke: idiopathic means the patient is pathological and the the doctor is an idiot Posts: 4676 | From western Montana | Registered: Apr 2009
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From Wikipedia, the free encyclopedia Interleukin-10 (IL-10 or IL10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. In humans IL-10 is encoded by the IL10 gene.
This cytokine is produced primarily by monocytes and to a lesser extent by lymphocytes. This cytokine has pleiotropic effects in immunoregulation and inflammation. It down-regulates the expression of Th1 cytokines, MHC class II antigens, and costimulatory molecules on macrophages. It also enhances B cell survival, proliferation, and antibody production. This cytokine can block NF-κB activity, and is involved in the regulation of the JAK-STAT signaling pathway. Knockout studies in mice suggested the function of this cytokine as an essential immunoregulator in the intestinal tract and indeed patients with Crohn's disease react favorably towards treatment with bacteria producing recombinant interleukin 10, showing the importance of interleukin 10 for counteracting excessive immunity in the human body.
A study in mice has shown that interleukin-10 is also produced by mast cells, counteracting the inflammatory effect that these cells have at the site of an allergic reaction.
-------------------- "They that are whole have no need for the physician, but they that are sick: I came not to call the righteous but sinners to repentance"(Mark 2.17) Posts: 149 | From Amsterdam | Registered: Jul 2011
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posted
Somewhere I read that IL-10 has more to do than downregulating inflammation. Will try to find that info.
Wondering if anyone is measuring IL-10 in chronic lyme patients? And if you measure it in the blood, does that reflect what is happening in the brain?
Aother question is whether you would want to downregulate inflammation when you have an intracellular infection.
Be nice if we had some real research in this area that had clinical application.
Posts: 8430 | From Not available | Registered: Oct 2000
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posted
Strle is one the authors of this study, and he is a no-chronic-lyme type.
Posts: 8430 | From Not available | Registered: Oct 2000
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Another question is whether you would want to downregulate inflammation when you have an intracellular infection.
Hello Lou, It seems that it improves the immune reaction: "Our results indicate that at times of high pathogen load, as during peak bacteremia in relapsing fever borreliosis, IL-10 protects innate immune cells from apoptosis via inhibition of TNF resulting in improved pathogen control." IL-10 helps control pathogen load during high-level bacteremia.
-------------------- "They that are whole have no need for the physician, but they that are sick: I came not to call the righteous but sinners to repentance"(Mark 2.17) Posts: 149 | From Amsterdam | Registered: Jul 2011
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posted
Well, here is an excerpt from a paper that makes it sound problematic. This is not the one I was mentioning earlier, still looking for it.
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"Similarly to many bacterial pathogens, Bordetella bronchiseptica, which has been used for the study of Bordetella pertussispathogenesis, manipulates the host immune response to promote its own survival by enhancing the production of the anti-inflammatory cytokine interleukin-10 (IL-10). A study by Nagamatsu et al.B. bronchiseptica."
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And it seems Bb also does this:
Viable Borrelia burgdorferi Enhances Interleukin-10 Production and Suppresses Activation of Murine Macrophages
John J. Lazarus, Maria A. Kay, Akisha L. McCarter, and R. Mark Wooten
Infection and Immunity, March 2008, p. 1153-1162, Vol. 76, No. 3
Department of Medical Microbiology and Immunology, University of Toledo Health Science Campus, Toledo, Ohio 43614
Although capable of eliciting strong innate and adaptive immune responses, Borrelia burgdorferi (Bb) often evades immune clearance through largely unknown mechanisms. Our previous studies determined that infected IL-10(-/-) mice show significantly lower Bb levels than wild type (B6) mice, and that IL-10 inhibits innate immune responses critical for controlling Bb infection.
To determine whether virulent Bb preferentially enhances IL-10 production, we developed an in vitro co-culture medium (RPMI.B) in which both Bb and primary macrophages (M�s) remain viable. Bb grew at similar rates and was able to regulate expression of immunoreactive proteins with similar kinetics in RPMI.B as bacteria grown in traditional BSK medium; in contrast, Bb cultured in conventional tissue culture medium (RPMI) rapidly lost viability.
Co-culture of viable Bb (RPMI.B) with M�s resulted in a more rapid and significant increase in IL-10 transcripts and secreted protein than co-cultures with non-viable Bb (RPMI), which corresponded with decreased production of proinflammatory cytokines.
Addition of live Bb to M�s in RPMI.B also elicited substantially higher IL-10 levels than did heat-killed bacteria, confirming that increased IL-10 production was not inherent to co-culture in RPMI.B.
Transfer of supernatants from Bb-stimulated M�s onto na�ve M� cultures resulted in suppressed activation upon subsequent stimulation with different bacterial agonists, and this suppression was obviated by IL-10-specific antibody.
In vivo analyses determined that murine skin samples exhibited a substantial upregulation of IL-10 within 24h of Bb injection. Together, these results suggest that viable Bb can suppress early M� responses during infection by causing increased release of IL-10.
posted
And it turns out this subject has been visited before, in 2008:
J Immunol. 2008 Aug 1;181(3):2076-83.
IL-10 helps control pathogen load during high-level bacteremia.
Londo�o D, Marques A, Hornung RL, Cadavid D.
Department of Neurology and Neuroscience and Center for Emerging Pathogens, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.
During relapsing fever borreliosis, a high pathogen load in the blood occurs at times of peak bacteremia.
Specific IgM Abs are responsible for spirochetal clearance so in absence of B cells there is persistent high-level bacteremia.
Previously, we showed that B cell-deficient mice persistently infected with Borrelia turicatae produce high levels of IL-10 and that exogenous IL-10 reduces bacteremia.
This suggested that IL-10 helps reduce bacteremia at times of high pathogen load by a B cell-independent mechanism, most likely involving innate immunity.
To investigate this possibility, we compared B. turicatae infection in RAG2/IL-10(-/-) and RAG2(-/-) mice.
The results showed that IL-10 deficiency resulted in significantly higher bacteremia, higher TNF levels, and early mortality.
Examination of the spleen and peripheral blood showed markedly increased apoptosis of immune cells in infected RAG2/IL-10(-/-) mice.
Neutralization of TNF reduced apoptosis of leukocytes and splenocytes, increased production of IFN-gamma by NK cells, increased phagocytosis in the spleen, decreased spirochetemia, and rescued mice from early death.
Our results indicate that at times of high pathogen load, as during peak bacteremia in relapsing fever borreliosis, IL-10 protects innate immune cells from apoptosis via inhibition of TNF resulting in improved pathogen control.
PMID: 18641346 [PubMed - indexed for MEDLINE]
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posted
So, frankly, it sounds like the jury is out as to whether adding IL-10 in some way would help or hurt.
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Pinelady
Frequent Contributor (5K+ posts)
Member # 18524
posted
Increase in IL10 prevents apoptosis(cell death), but at the expense of TLRs which induce cytokines to fight.
They turn off TLR's so there is no reaction.
No reaction the cells are subject to even more infections due to no cytokine response..
You get sick sick sick---but you don't look sick.
-------------------- Suspected Lyme 07 Test neg One band migrating in IgG region unable to identify.Igenex Jan.09IFA titer 1:40 IND IgM neg pos 31 +++ 34 IND 39 IND 41 IND 83-93 + DX:Neuroborreliosis Posts: 5850 | From Kentucky | Registered: Dec 2008
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Pinelady
Frequent Contributor (5K+ posts)
Member # 18524
posted
This is also a huge mistake they have gotten away with reporting in vaccines...
Cherry pickers did not report...
-------------------- Suspected Lyme 07 Test neg One band migrating in IgG region unable to identify.Igenex Jan.09IFA titer 1:40 IND IgM neg pos 31 +++ 34 IND 39 IND 41 IND 83-93 + DX:Neuroborreliosis Posts: 5850 | From Kentucky | Registered: Dec 2008
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