The investigators model inflammation (a central element of all disease states) through the use of treatment with interferon (IFN)-alpha, which provides a standardized regimen of chronic cytokine exposure known to produce profound behavioral disturbances, including depression, fatigue and sickness, in a high percentage of individuals.
Full Answer
What is the pathogenicity of the IFNα treatment?
· Inflammation-mediated downregulation of IFNα-2AR1 is associated with refractoriness to rIFNα. 49 Noteworthy in this context is that the inflammatory cytokines interleukin 1-alpha (IL-1-α) and tumor necrosis factor alpha (TNF-α) stimulate IFNα-2AR1 degradation and accordingly attenuate IFNα-2a signaling. 48 Similarly, unresponsiveness to …
Does IFNλ therapy promote antiviral gene induction without increasing immune cell stimulation?
· Immune activation is also associated with chronic inflammation and activation of the coagulation system that increase the risk of ‘serious non-AIDS events' such as atherosclerotic vascular disease, osteoporosis, osteonecrosis and chronic kidney disease. 1 Inflammation also affects lymphoid tissue where the resultant tissue fibrosis is a cause ...
What is the difference between IFNα and IFNλ?
Increased concentrations of TNF-alpha are found in acute and chronic inflammatory conditions (e.g., trauma, sepsis, infection, rheumatoid arthritis), in which a shift toward a proatherogenic lipid profile and impaired glucose tolerance occurs. Although therapeutic blockade of TNF-alpha worsens the prognosis in patients with abscesses and granulomatous infections, this strategy …
What is the role of IFN-α in the treatment of HIV infection?
Interferon-alpha & Inflammation: interferon stimulates activation/inflammation, therapies to quell activation Download the PDF here see paper below pdf attached: "Another potent trigger …
Is IFN-alpha anti-inflammatory?
Initially thought to have mainly immunomodulating and proinflammatory effects, recent data suggest that IFN alpha has several anti-inflammatory properties. These newly identified anti-inflammatory and immunosuppressive functions may help to explain some of the IFN mechanisms.
What does IFN-alpha do?
IFN-α is an antiviral cytokine of the type I IFN innate immune response of most cell types. IFN-α exhibits anti-viral activity via the induction of protective genes that inhibit viral replication and impede viral dissemination.
Does IFN cause inflammation?
The innate immune response is involved in various inflammatory processes and has a particularly important role in bacterial and viral infections. Interferons (IFNs) and inflammatory cytokines are crucial molecules in this process, influencing cellular, tissue, and global physiological functions.
What does interferon do during an inflammatory response?
Interferons were first described as an antiviral factor that interferes with viral replication in mammalian cells (10). They are secreted from infected cells and activate innate immune response that promotes not only cytokine production but also natural killer cell functions and antigen presentation (11, 12).
Why are some patients treated with alpha interferons?
Interferon alpha helps stimulate the body's immune system to fight some types of cancer by strengthening the immune system, reducing the ability of the cancer cells to defend themselves from the immune system and by slowing down or stopping the cancer cells from dividing.
How does interferon treatment work?
Interferons are man-made versions of proteins your body makes. These drugs work with your immune system to help it find and attack viruses and cancer. They can stop virus and cancer cells from growing and spreading, and prevent other cells from getting infected.
Is IFN-gamma pro-inflammatory?
IFN-γ is a proinflammatory cytokine involved in Th1-driven immune responses.
What cytokines are involved in inflammation?
The key pro-inflammatory cytokines are IL-1, IL-6, and TNF-α. These cytokines signal via type I cytokine receptors (CCR1) that are structurally divergent from other cytokine receptor types. They are crucial for coordinating cell mediated immune response and play a critical role in modulating the immune system.
What do type 1 interferons do inflammation?
An important driver of inflammation in the lung is the interferon (IFN) response. Type I IFNs are antiviral cytokines that induce a large range of proteins that impair viral replication in infected cells. This cell-intrinsic action plays a crucial role in protecting the lungs from spread of respiratory viruses.
What happens during inflammatory response?
The inflammatory response (inflammation) occurs when tissues are injured by bacteria, trauma, toxins, heat, or any other cause. The damaged cells release chemicals including histamine, bradykinin, and prostaglandins. These chemicals cause blood vessels to leak fluid into the tissues, causing swelling.
What produces pro inflammatory cytokines?
Pro-inflammatory cytokines. Proinflammatory cytokines are produced predominantly by activated macrophages and are involved in the up-regulation of inflammatory reactions. There is abundant evidence that certain pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α are involved in the process of pathological pain.
How do interferons increase resistance to viral infections?
Via interferons Virally infected cells produce and release small proteins called interferons, which play a role in immune protection against viruses. Interferons prevent replication of viruses, by directly interfering with their ability to replicate within an infected cell.
What is the role of TNF-alpha in chronic inflammation?
The role of TNF-alpha in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. The recent insight that inflammation contributes to the development of atherosclerosis and type 2 diabetes mellitus constitutes a major breakthrough in understanding the mechanisms underlying these conditions.
What is the cause of increased TNF-alpha levels?
Increased concentrations of TNF-alpha are found in acute and chronic inflammatory conditions (e.g., trauma, sepsis, infection, rheumatoid arthritis), in which a shift toward a proatherogenic lipid profile and impaired glucose tolerance occurs.
Does inflammation cause diabetes?
The recent insight that inflammation contributes to the development of atherosclerosis and type 2 diabetes mellitus constitutes a major breakthrough in understanding the mechanisms underlying these conditions. In addition, it opens the way for new therapeutic approaches that might eventually decrease the prevalence of these public health problems.
Does TNF-alpha blockade affect rheumatoid arthritis?
Although therapeutic blockade of TNF-alpha worsens the prognosis in patients with abscess es and granulomatous infections, this strategy is highly beneficial in the case of chronic inflammatory conditions, including rheumatoid arthritis.
Abstract
Owing to the unique opportunity to assess individuals before and after they develop depression within a short timeframe, interferon- α (IFN- α) treatment for chronic hepatitis C virus (HCV) infection is an ideal model to identify molecular mechanisms relevant to major depression, especially in the context of enhanced inflammation.
Introduction
The development of clinically significant depression during interferon- α (IFN- α) therapy for chronic hepatitis C virus (HCV) infection is common, with an incidence of up to 45% ( Asnis and De La Garza, 2006 ).
Materials and methods
This was a prospective cohort study, evaluating patients at baseline and monthly over 24 weeks of IFN- α treatment.
Results
We first examined differences in gene expression at baseline (before starting IFN- α) and compared the profile of patients who subsequently did and who did not develop IFN- α -induced depression.
Discussion
To our knowledge, this is the first study to use a peripheral blood transcriptomics approach to identify both predictors of future development of IFN- α -induced depression and biological pathways associated with the development of depression.
Funding and disclosure
Professor Pariante and Dr Mondelli have received research funding from Johnson & Johnson as part of a program of research on depression and inflammation.
Acknowledgements
This work was supported by the grant ‘Persistent Fatigue Induced by Interferon-alpha: A New Immunological Model for Chronic Fatigue Syndrome’ (MR/J002739/1) and by the grant ‘Immuno-psychiatry: A Consortium to test the Opportunity for Immunotherapeutics in Psychiatry’ (MR/L014815/1), from the Medical Research Council (UK).
What is type I interferon?
Type I interferon (IFN), mainly IFN-α and IFN-β, are important antiviral cytokines that also have complex roles in regulating inflammation. They may enhance immune responses contributing to effective viral clearance, but excessive activation of type I IFN production may lead to chronic inflammatory conditions, such as systemic lupus erythematosus (SLE) [ 1 ]. Conversely, type I IFN can dampen inflammatory conditions such as multiple sclerosis MS [ 2] and experimental models of colitis [ 3 ]. We earlier showed that injection of interferogenic dsRNA or IFN-α into a healthy mouse joint induces transient arthritis, which may explain why arthritis may follow viral infections [ 4 ]. In contrast, we also showed that if interferogenic dsRNA or IFN-α is coadministered at repeated immunizations with methylated bovine serum albumin, it totally prevents subsequent induction of antigen-induced arthritis [ 5 ].
Does IFN- help with arthritis?
To understand this tolerogenic mechanism, we performed a descriptive , hypothesis-generating study of cellular and humoral responses associated with IFN-α-mediated protection against arthritis.
Does IFN- inhibit TNF?
Administration of IFN-α protected mice from arthritis in a dose-dependent manner but had no effect on antigen-specific antibody levels. However, IFN-α did inhibit the initial increase of IL-6, IL-10, IL-12, and TNF, and the recall response induced by intraarticular mBSA challenge of IL-1β, IL-10, IL-12, TNF, IFN-γ, and IL-17 in serum. IFN-α decreased both macrophage and CD4 + T cell-derived IFN-γ production, whereas IL-17 was decreased only in CD4 + T cells. Ex vivo, in mBSA-restimulated spleen and lymph node cell cultures, the inhibitory effect of in vivo administration of IFN-α on proinflammatory cytokine production was clearly apparent, but had a time limit. An earlier macrophage-derived, and stronger activation of the antiinflammatory cytokine transforming growth factor beta (TGF-β) was observed in IFN-α-treated animals, combined with an increase in CD4 + T cells producing TGF-β when arthritis was triggered by mBSA (day 21). Presence of IFN-α at immunizations also prevented the reduction in TGF-β production, which was induced by the intraarticular mBSA injection triggering arthritis in control animals.
Does IFN affect antigen production?
Administration of IFN-α has a profound effect on the cellular response to mBSA plus adjuvant, but does not affect antigen-specific Ig production. By including IFN-α at immunizations, spleen and lymph node cells inhibit their repertoire of antigen-induced proinflammatory cytokines while enhancing antiinflammatory TGF-β production, first in macrophages, and later also in CD4 + T cells. On intraarticular antigen challenge, this antiinflammatory state is reenforced, manifested as inhibition of proinflammatory recall responses and preservation of TGF-β levels. This may explain why IFN-α protects against antigen-induced arthritis.
What is the IFN subtype?
All type I IFN subtypes act through a common, ubiquitously expressed, heterodimeric receptor (IFNαβR) to induce the transcription of a diverse set of genes known as IFN-stimulated genes (ISGs) (Randall & Goodbourn, 2008 ). In particular, type I IFN induces the expression of IFN-inducible transmembrane protein 3 (IFITM3), IFN-regulatory factor 7 (IRF7) and orthomyxovirus resistance gene (Mx) family proteins, all bona fide restriction factors of IAV (Everitt et al, 2012; Ciancanelli et al, 2015; Haller et al, 2015 ).
Why is it important to understand the multiple effects of interferons?
Understanding the multiple effects of interferons is important when considering them as therapeutic options against influenza.
What is FCI-MH?
All protocols for breeding and experiments with animals were approved by the local ethics committee of the Francis Crick Institute, Mill Hill Laboratory (FCI-MH), and by the Home Office, UK, under the Animals (Scientific Procedures) Act 1986 and project licence 70/7643. For in vitro experiments with human immune cells, peripheral venous blood was obtained from six healthy adult volunteers. A properly executed, written, and FCI-MH review board-approved informed consent was obtained from each volunteer before blood collection. All samples were collected according to protocols approved by the FCI-MH.
Does IFN affect IAV replication?
IFNλ controls IAV replication and consequently diminishes infection-induced morbidity. However, why does IFNα treatment translate into increased, not decreased morbidity, despite equivalent control of IAV replication exerted by IFNα as by IFNλ? The explanation for the pathogenicity of the IFNα treatment is increased inflammation through activation and recruitment of immune cells. This hypothesis is supported by increased inflammatory cytokines in BAL fluids, augmented pDC and inflammatory monocyte frequency in the lung and elevated apoptosis of airway epithelial cells following IFNα but not IFNλ treatment. Furthermore, bone marrow-derived macrophages, cDCs and pDCs secreted proinflammatory cytokines in vitro only in response to stimulation with IFNα, yet not IFNλ. Importantly, IFNαβ-induced inflammation and AEC apoptosis are immune mechanisms which, when controlled, contribute to limiting the spread of IAV, yet in an immunocompetent system, addition of exogenous IFNα may overactivate these mechanisms resulting in cytokine storm, increased inflammatory cell recruitment, higher frequency of AEC death and ultimately, host mortality. By clustering the response to exogenous IFN treatment into IFNα-specific genes and genes induced by both IFNα and IFNλ, we have determined that the pathogenic component driving the hypercytokinemia is specific to IFNα and not common to IFNα and IFNλ. The IFNα-specific gene signature most likely originates from the IFNα-mediated activation of immune cells. This is corroborated both by the lack of production of proinflammatory cytokines by cultured mouse AEC (in this study) and by studies showing a virtually identical gene induction profile between IFNα and IFNλ in cultured murine and human AEC (Crotta et al, 2013; Lauber et al, 2015 ).
Does IFN affect ISGs?
To translate our results into human cells, we generated human primary AEC cultures and found that both IFNα and IFNλ treatments induced the upregulation of antiviral ISGs such as Rsad2, OAS1 and Mx1 (Fig 5 A), as in mouse AEC cultures. PBMCs from healthy donors upregulated ISGs in response to IFNα at both 4 and 24 h (Fig 5 B), yet not in response to an equipotent dose of IFNλ. Importantly, analysis of cytokine induction by each IFN treatment at 4 and 24 h revealed that IFNα induced secretion of many proinflammatory cytokines including IL-6, MCP-1 and IP-10, while IFNλ treatment did not (Fig 5 C). Collectively, these data indicate that IFNλ treatment of IAV-infected humans is unlikely to drive a cytokine storm and may therefore be a viable treatment option.
Is IFN treatment realistic?
Pretreatment with IFNs is not a realistic clinical option to protect the population during a large-scale pandemic as patients seek medical intervention only after clinical onset. We therefore assessed the effectiveness of IFNα and IFNλ at ameliorating disease when administered after IAV infection (Fig 1 D). Mice were infected with PR8 and treated after onset of clinical signs intranasally with IFNα, IFNλ or vehicle control on days 2, 4 and 5 post-infection. IFNλ-treated mice exhibited significantly lower mortality compared to vehicle control group. In striking contrast, IFNα treatment exacerbated disease causing higher mortality than in infected, vehicle-treated mice (Fig 1 D). The divergent disease outcome between the IFN treatment groups was not due to different antiviral activity, as treatment-induced reduction in viral load in the lung was similar (Fig 1 E).
Does IAV cause lung damage?
IAV-induced mortality in humans does not always correlate with high viral load, yet it is always associated with cytokine storm and tissue damage (Peiris et al, 2004; de Jong et al, 2006; Louie et al, 2009; Agrati et al, 2010; Arankalle et al, 2010 ). This highlights that AEC apoptosis and therefore lung damage in IAV infection can be caused by both host immunity- and virus-mediated cytotoxicity, and indicates that safe and successful treatment should combat the virus without further immunostimulation. IFNλ therapy fulfils these criteria as it enhances IAV clearance and thus protects from virus-induced AEC apoptosis, without exacerbating those facets of the immune response that also instigate AEC death.
How to reduce inflammation?
Medication, supplements, and eating an anti-inflammation diet can help you reduce your risk of inflammation. Avoiding smoking and alcohol, and maintaining a healthy body weight can also help lower your risk, along with reducing your stress levels. Last medically reviewed on July 27, 2018.
What is chronic inflammation?
an autoimmune disorder, which involves your immune system mistakenly attacking healthy tissue. Keep in mind that these don’t cause chronic inflammation in everyone. In addition, some cases of chronic inflammation don’t have a clear underlying cause.
What foods are good for inflammatory disease?
These include foods that are high in antioxidants and polyphenols, such as: olive oil. leafy greens, such as kale and spinach. tomatoes. fatty fish, such as salmon, sardines, and mackerel. nuts.
Does chronic inflammation increase your risk of serious diseases?
Chronic inflammation can increase your risk of several serious diseases.
What foods cause inflammation?
The following foods can increase inflammation in some people: refined carbohydrates, such as white bread and pastries. fried foods, such as French fries. red meat. processed meat, such as hot dogs and sausage. If you’re trying to reduce fight inflammation, try to reduce your intake of these foods.
Is inflammation a natural part of healing?
Inflammation is a natural part of the healing process. But when it becomes chronic, it’s important to try to get it under control to reduce your risk of long-term damage. Some of the options that’ve been explored for managing inflammation include:
What are the effects of corticosteroids on the immune system?
Steroids. Corticosteroids are a type of steroid hormone. They decrease inflammation and suppress the immune system, which is helpful when it starts attacking healthy tissue.