Cytokine pdf

Any given cytokine may have many different biologic effects. The mode of action of many of the cytokines involves typical signal transduction events such as protein phosphorylation, and to date there is only limited understanding of the mechanisms that lead to one activity over another when a specific cytokine is involved in a specific biologic reaction.

Nevertheless, elucidation of their role in other pathologic processes has provided insight into autoimmune and allergic diseases, as well as a variety of systemic disorders. Several lines of evidence have revealed that cytokines play important roles not only in tissue homeostasis but also in the pathogenesis of many infectious diseases.

Cytokines play crucial roles in the maintenance of tissue homeostasis, a process which requires a delicate balance between anabolic and catabolic activities.

Table 4: Cytokine Function []. Th2, and Th17 responses Innovative Immunology www. Subsequent cascades of intracellular signaling then alter cell functions []. The effect of a particular cytokine on a given cell depends on the cytokine, its extracellular abundance, the presence and abundance of the complementary receptor on the cell surface, and downstream signals activated by receptor binding, these last two factors can vary by cell type.

It seems to be a paradox that cytokines binding to antibodies have a stronger immune effect than the cytokine alone. This may lead to lower therapeutic doses [] showing that inflammatory cytokines cause an ILdependent inhibition of T cell expansion and function by up-regulating PD-1 levels on monocytes which leads to IL production by monocytes after binding of PD-1 by PD-L. Occasionally such reactions are seen with more widespread papulareruptions []. Table 6: Cytokine Function [].

Cytokines are important mediators of immune responses that allow integration of the behavior of cells in time and geographical location as the immune responses are generated [56]. The immune system is organized into innate and adaptive immune responses, with adaptive immunity further subdivided into two branches, humoral and cell-mediated immunity [95,,]. Innate immunity is immediate and rapid.

Innate defense mechanisms include neutrophils and macrophages, which, among other functions, can ingest and destroy pathogens. While often effective in protecting the host, innate immunity is associated with damage to host tissue in the context of providing defense. It is also amnestic in that the inciting agent is not specifically recognized by a unique structure and there is no creation of a memory to that agent such that future responses are more efficient [].

Adaptive immunity is slower in its response to threats. However, it provides two main features that innate immunity lacks: specific antigen recognition and memory that allows rapid recall of original antigen exposure. Host defense is generally provided in two major arms of the adaptive response [95,,] Resistance to Trypanosoma cruzi infections is critically dependent on cytokine-mediated activation of cell-mediated immune effector mechanisms.

In addition, IL synthesized by infected or LPS-stimulated macrophages, in addition to other actions, stimulates cytokine synthesis by both NK and T helper cells and promotes the activation and expansion of these lymphocyte subpopulations []. Reciprocal regulatory interactions among cytokines secreted by the innate and acquired immune systems ultimately control the activation of each system and its cytokine-mediated effector functions. White blood cells and certain other cells of the immune system produce cytokines when an antigen is detected [].

They stimulate certain white blood cells to become more effective killers and to attract other white blood cells to a trouble spot []. Cytokines have a multitude of different biological effects and are very important both in the innate and in the adaptive immune response [].

Cytokines bind to specific receptors on target cells with high affinity and the cells that respond to a cytokine are either: 1 the same cell that secreted cytokine autocrine ; 2 a nearby cell paracrine or 3 a distant cell reached through the circulation endocrine.

It is an important mediator of acute inflammation. Interleukin 1 IL-1 is another inflammatory cytokine produced by activated macrophages. Interleukin 10 IL is produced by activated macrophages and Th2 cells. It is predominantly an inhibitory cytokine []. Interleukin 12 IL is produced by activated macrophages and dendritic cells. In addition, it enhances the cytolytic functions of Tc and NK cells [].

Type I interferons also activate NK cells []. Chemokines are chemotactic cytokines produced by many kinds of leukocytes and other cell types [7]. Interleukin 2 IL-2 is produced by Th cells, although it can also be produced by Tc cells to a lesser extent.

It is the major growth factor for T cells. It also promotes the growth of B cells [,]. Interleukin 4 IL-4 is produced by macrophages and Th2 cells.

It also stimulates Ig class switching to the IgE isotype []. Interleukin 5 IL-5 is produced by Th2 cells and it functions to promote the growth and differentiation of B cells and eosinophils. It also activates mature eosinophils []. It is primarily an inhibitory cytokine.

It inhibits the proliferation of T cells and the activation of macrophages. It also acts on PMNs and endothelial cells to block the effects of pro-inflammatory cytokines [].

Some cytokines stimulate the differentiation of hematopoetic cells. Soluble antibody can compete with antigen receptors on B cells and block or prevent B cell activation. In addition antigen antibody complexes can bind to Fc receptors on B cells, sending an inhibitory signal to B cells []. The release of cytokines is central to almost every stage of the immune response to allergens.

IL-4 and IL13 also affect B cells to produce allergen specific antibodies. Cytokine production is important for both the early and late phases of the asthmatic reaction. Finally, cytokine actions are important for the excessive inflammation and airway remodeling that characterizes late phase asthmatic reactions IL-5, IL-9, IL, TNF []. An enhanced Th2 immune response and the elaboration of cytokines such as IL-4, IL13, and IL-5 contribute to the induction of allergy and asthma.

The mechanisms leading to an enhanced Th2 response are still controversial. Th2-dominated immune responses may result from immune suppression of T-regulatory cells as well as Th1 cells.

Understanding early-life immune mechanisms responsible for atopic diseases, specifically how cytokines of T-regulatory cells act to balance the Th1 and Th2 immune response, continues to be a fruitful area of research [].

Table 7: Characteristics of cytokines implicated in the innate response []. It comprises a non-invasive, easy, and rapid to collect, and yet, a cost-effective specimen. Plasma levels of various cytokines may give information on the presence, or even predictive value of inflammatory processes involved in autoimmune diseases such as rheumatoid arthritis [] as well as immunomodulatory effects of foods or drugs [].

In addition, elevated levels of IL-7, an important cytokine involved in T cell homeostasis, have been detected in the plasma of HIV-infected patients []. It has been proven that certain cytokines are produced by oral squamous cell carcinoma OSCC cells. When the validity of IL-8 and -6 as biomarkers for OSCC diagnosis has been investigated, analysis of their levels in saliva of a group of 32 patients and 32 healthy controls, and in serum of 19 patients and 32 healthy controls, revealed high sensitivity and specificity of using salivary IL-8 and serum IL-6 levels simultaneously for predicting OSCC [].

Rhodus et al. Serum soluble interleukin-6 receptor sIL-6R concentrations were measured in 50 patients with plasma cell dyscrasias using a commercially available immunoenzymatic assay kit. They conclude that elevated serum sIL-6R levels should be related to the growth of myeloma cells and suggest that serum sIL-6R concentrations may be used as an indicator of disease activity [].

Cytokines are a unique class of intercellular regulatory proteins that play a crucial role in initiating, maintaining, and regulating immunologic homeostatic and inflammatory processes. Indeed, measurement of cytokine profiles in patients provides a useful indication of disease status. Due to their multiple functions, including regulatory and effector cellular function in many diseases, these molecules, their receptors, and their signal transduction pathways are promising candidates for therapeutic interference [].

Overall, the study reports a large-scale analysis of cytokines for enhancing the IFN response, and identified cytokines capable of enhancing Stat1, IFN-induced gene expression, and antiviral activities []. The chemokine system in cancer therapy acts as we know that chemokines are a key component of cancer-related inflammation. Chemokines and chemokine receptors are downstream of genetic events that cause neoplastic transformation and are components of chronic inflammatory conditions, which predispose to cancer.

Components of the chemokine system affect in a cell autonomous or non- autonomous way, multiple pathways of tumor progression include: leukocyte recruitment and function; cellular senescence, tumor cell proliferation and survival, invasion and metastasis []. Components of the chemokine system affect multiple pathways of tumor progression including: leukocyte recruitment, neo-angiogenesis, tumor cell proliferation and survival, invasion and metastasis [].

Chemokines and chemokine receptors are being investigated for their role in tumor development and metastasis and may prove to be useful therapeutic targets. The chemokine family is a complex network of molecules that are ubiquitously expressed and perform a variety of functions most notably regulating the immune system [].

Pro-inflammatory cytokines, such as interleukin-1b IL-1b , interleukin-6 IL-6 and tumor necrosis factor- TNF-a play an essential role in the regulation of immune response and may have prognostic significance in cancer.

The mean concentrations of SCC were also elevated. IL-6 and sTNF-RI seemed to be the most sensitive parameters in early stages and may be used as additional markers in oral cancer [,] indicated that cytokines and soluble cytokine receptors, both physiologically involved in bone destruction and bone formation, have an essential role in the progression of malignant bone tumors.

Strong correlations between the occurrence of hematological abnormalities and elevated serum levels of several cytokines and soluble cytokine receptors, suggest that the former may develop as a result of cytokine misbalance frequently detected in soft tissue sarcoma patients.

However, the results of routine blood tests alone are no independent prognostic factor for survival of soft-tissue sarcoma patients []. The majority of studies indicate that interferons are used mainly in the immunotherapy for multiple myeloma, whereas many clinical trials should still be required for the evaluation of the effectiveness of anti-I-L6 antibodies or antiidiotypic vaccines in reference to the eligible patients for these particular therapies [].

The therapeutic administration of cytokines, modulation of cytokine action, or at times gene therapy is being used for a wide range of infectious and autoimmune diseases, in immunocompromised patients with AIDS, and in neoplasia []. Cytokines are often involved in several developmental processes of immune system during embryogenesis. Cytokines are take part in fighting off infections and in other immune responses as proinflammatory []. Another important example of cytokine storm is seen in acute pancreatitis [,].

Cytokines are integral and implicated in all angles of the cascade resulting in the systemic inflammatory response syndrome and multi organ failure associated with this intra-abdominal catastrophe []. Some cytokines have been developed into protein therapeutics using recombinant DNA technology [4].

Cytokines have been widely tested in clinical trials during recent years and beneficial responses have been observed in a variety of malignant, infectious and autoimmune diseases. Interferon-alpha induces remissions in patients with certain hematological malignancies such as hairy cell leukemia and chronic myelogenous leukemia.

A proportion of patients with chronic viral hepatitis is cured upon application of interferon alpha. Treatment with interferon-gamma reduces the number of infections in patients with chronic granulomatous disease. In addition, several chronic infections with intracellular pathogens also respond to treatment with this cytokine. With the exception of some patients with renal cell carcinoma and malignant melanoma, solid tumors are largely resistant to administration of these cytokines.

Cytokine treatment has changed the outlook for a small group of patients with selected chronic diseases []. Alpha-interferons have been widely used as a therapeutic agent.

Interferons alpha have antiviral, anticancer and immunomodulatory activities. Clinical trials have proved interferons alpha to be of special value as adjuvant therapy first line drugs for hairy cell leukemia, virus hepatitis B and C and condylomata acuminata.

Interferon alpha is an important advanced modality in the management of chronic myelogenous leukemia and can be considered a first-line therapy option in patients who cannot receive or relapse following allogenic bone marrow transplant. Clinical trials have proved interferons alpha to be of special value as first line drugs for hairy cell leukemia, virus hepatitis B and C and condylomata accuminata.

Interferon alpha is used as single primary therapy, adjuvant therapy and maintenance therapy. The limiting factor for the application of interferons alpha is the cost of treatment []. Two forms of alpha interferon, interferon alfa-2b and interferon alfa-2a, has been approved for used in Australia.

Interferon alfa-n1 is not Innovative Immunology www. The use of the alpha interferons is currently under investigation in a wide variety of other diseases, with the likelihood that other indications will soon be established. However, the alpha interferons are generally not regarded as first line agents. Beta and gamma interferons have been studied less intensively than the alpha interferons, but it is likely that selected applications for their use will also be defined with the passage of time [].

The emergence of genetically engineered biological agents opened new prospects in the treatment of autoimmune and inflammatory diseases. Cytokines responsible for regulation of a wide range of processes during development of the normal immune response are among the most successful therapeutic targets []. Saad, , [] indicated a complex interplay of oxidative stress, endothelial dysfunction, and activation of fibrogenic and inflammatory cytokines as a result of atherosclerosis, hypoxia, and renal hypoperfusion in this disorder.

Human studies emphasize the limits of the kidney adaptation to reduced blood flow, eventually leading to renal hypoxia with activation of inflammatory and fibrogenic pathways. Although these cytokines provide potential therapeutic targets for PTA, intra-articular injections of anti-cytokine therapies have proven difficult due to rapid clearance from the joint space. They found that IL-1 plays a critical role in the pathogenesis of PTA following articular fracture, and sustained intra- articular cytokine inhibition may provide a therapeutic approach for reducing or preventing joint degeneration following trauma [].

The pro-inflammatory cytokines are the prime targets of the strategies to control rheumatoid arthritis RA. The activity of pro-inflammatory cytokines can also be down regulated either by using specific siRNA to inhibit the expression of a particular cytokine or by using small molecule inhibitors of cytokine signaling [].

Collectively, it seems that IL-1 and IL-6 are promising targets in patients refractory or intolerant to other regimens including anti-TNFs. However, controlled studies are surely needed []. Novel treatments in development for rheumatoid arthritis target 3 broad areas: cytokines, cells, and signaling pathways []. Targeted local inhibition of IL-1 following joint injury may represent a novel treatment option for Post-traumatic arthritis []. Due to the crucial role of inflammatory cytokines in the pathogenesis of autoimmune disorders, anti- cytokine treatment has been developed as atherapy for rheumatoid arthritis, juvenile idiopathic arthritis JIA , and inflammatory bowel diseases [,].

Dischereit and Lange, [] explained early interventions to preserve bone health, for example, by anti-cytokine therapy. It is necessary to produce new therapeutics for non-responders in whom serum ILA levels are still higher against long-term SLIT []. There is much interest in potential therapeutics that promote remyelination and here we explore use of leukaemia inhibitory factor LIF , a cytokine known to play a key regulatory role in self-tolerant immunity and recently identified as a pro-myelination factor [].

The experimental model used in this study shown to be appropriate for creation of acute pancreatitis. It was concluded that oleuropein as a prophylactic treatment has no protective effect on serum proinflammatory and anti-inflammatory cytokines as well as pancreatic tissue. Bladders and kidneys of AKB treated mice developed less inflammation as evidenced by decreased pro-inflammatory cytokine release and neutrophil activity.

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Cytokines perform this function. Cytokines are a large, diverse family of small proteins or glycoproteins usually smaller than 30 kDa. Although initially described for their immunomodulatory capabilities, additional roles separate from the immune system in developmental processes are also documented, such as cell differentiation and directed migration.

Influencing both innate and adaptive immune responses, the two principal producers of cytokines are helper T cells Th cells and macrophages , although they can be transiently induced and secreted by virtually all nucleated cells.

The downstream effects of a particular cytokine occurs through its high-affinity binding of its receptor expressed on the surface of a target cell. This action may occur in an autocrine acts on same cell , paracrine acts on nearby cell or endocrine acts on distant cell; not the normal manner for cytokine responses manner. Receptor engagement triggers intracellular signalling cascades leading to altered gene expression in the target cell, which lead to a biological effect Figure 1.

Differentiation, proliferation and activation of the target cell are all effects which can be detected after cytokine stimulation. The multiple cytokines detected in the extracellular milieu at any given time during an immunological response can interact in pleiotropic different effects on different types of target cells , redundant multiple cytokines have same effect , synergic cooperative effect of multiple cytokines , antagonistic inhibition of one cytokines effects by another and cascade induction multiple-step feed-forward mechanism for the amplified production of a particular cytokine manners.

These interactions make it possible for the coordinated recruitment and activation of an entire network of immune cells by a relatively small number of cytokines produced by a single cell type e. In healthy individuals, cytokine action is regulated by their transient production only in response to either antigen or potent inflammatory stimuli, the short half-life of cytokines in extracellular fluids and compartments, and the restricted receptor expression profiles on the surface of both activated and unactivated target cells, as well as other mechanisms.

Of course, there are examples of cytokine dysregulation which result in pathological disease. Colony stimulating factors CSF are part of the haematopoietin family of cytokines. CXCL10 induces the migration of Th1 cells from areas of low CXCL10 concentrations towards areas with high concentrations of the molecule, such as the site of an infection and inflammation Figure 3.