The products of the heme oxygenase reaction, free ferrous iron, carbon monoxide, and biliverdin/bilirubin, are all biologically active molecules that may profoundly influence tissue redox homeostasis under a wide range of pathophysiological conditions.
The ho-1 gene is also upregulated in glial cells within multiple sclerosis plaques
Under pathological conditions, microglia produce proinflammatory mediators which contribute to neurologic damage, and whose levels can be modulated by endogenous factors including neurotransmitters such as norepinephrine
The epigenetic marks a person has could influence disease directly, but they also could affect whether an underlying genetic mutation or genetic variation can actually result in biologic or physiologic changes," says Bjornsson, a physician from Iceland who is pursuing his Ph.D. in human genetics at Hopkins. "We think the latter is going to be very important in explaining the variability of the most common diseases."
For example, if a disease-causing mutation is present in a gene turned "off" by its epigenetic marks, then the mutation can't cause disease. More subtly, alteration of epigenetic marks could "tune" gene expression to cause a full spectrum of effects. Epigenetic variation is also likely to help relate environment and age to disease incidence and risk, the researchers say
Matrix metalloproteinases (MMPs) constitute a large family of Zn2+- and Ca2+-dependent endopeptidases, implicated in tissue remodeling and chronic inflammation. They possess broad and overlapping specificities and collectively have the capacity to degrade all the components of the ECM (42, 52). MMPs are produced by many cell types, including lymphocytes and granulocytes, but in particular by activated macrophages (17). MMPs are secreted as proenzymes, which are activated by proteolytic cleavage and regulated by a family of inhibitors called the tissue inhibitors of matrix metalloproteinases (TIMPs), which are constitutively produced by a variety of cells. Changes in actual MMP activity are thus dependent on the balance between production and activation of MMPs and the local levels of TIMPs. In rheumatoid arthritis, pulmonary emphysema, periodontal disease, and inflammatory bowel disease, MMPs are believed to be responsible for much of the associated tissue destruction (4, 35, 43, 50). In addition to their direct effects on ECM proteins, MMPs can exacerbate inflammation by activating the proinflammatory cytokine interleukin-1b (IL-1b) or releasing cytokines such as TNF-a and IL-6 from cell surfaces (1, 21, 23). Their generation of chemotactic fragments from ECM proteins may also contribute to the recruitment of inflammatory cells (22, 40).
MMP-9 is suggested to contribute to destruction of the blood-brain barrier and to neuronal injury
Parenteral administration of interferon (IFN)-beta is one of the currently approved therapies for multiple sclerosis. One characteristic of this disease is the increased production of gelatinase B, also called matrix metalloproteinase (MMP) 9. Gelatinase B is capable of destroying the blood-brain barrier, and of cleaving myelin basic protein into immunodominant and encephalitogenic fragments, thus playing a functional role and being a therapeutic target in multiple sclerosis. Here we demonstrate that gelatinase B proteolytically cleaves IFN-beta, kills its activity, and hence counteracts this cytokine as an antiviral and immunotherapeutic agent. This proteolysis is more pronounced with IFN-beta-1b than with IFN-beta-1a. Furthermore, the tetracycline minocycline, which has a known blocking effect in experimental autoimmune encephalomyelitis, an in vivo model of acute inflammation in multiple sclerosis, and other MMP inhibitors prevent the in vitro degradation of IFN-beta by gelatinase B. These data provide a novel mechanism and rationale for the inhibition of gelatinase B in diseases in which IFN-beta has a beneficial effect. The combination of gelatinase B inhibitors with better and lower pharmacological formulations of IFN-beta may reduce the side-effects of treatment with IFN-beta, and is therefore proposed for multiple sclerosis therapy and the immunotherapy of viral infections.
Specifically, decreased TIMP1 gene expression in the autoimmunity signature suggests increased MMP activity in target tissues as a result of the lack of feedback mechanism.
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