Set of proteins that regulate interactions of the cells of the immune system. Its immunoregulatory function is key in the immune response, in inflammation and in the hematopoiesis of different cell types.
Function
They are glycoproteins or low molecular weight proteins produced during the initiation phase or in the effector phase of the immune response in order to mediate and regulate the amplitude and duration of the immune / inflammatory responses. The complex interactions between cells for an effective immune response are mediated by a series of secreted low molecular weight proteins that are collectively known as cytokines which function as messengers of the immune system: they regulate the intensity and duration of the immune response, stimulating or inhibiting the proliferation of various cells, the secretion of antibodies or other cytokines.
They are produced by the activation of leukocytes and also by the activation of neural cells, fibroblasts, and endothelial cells. * The activation of these cells is one of the earliest events in the cellular response to tissue damage. Another very important stimulus against tissue damage is the neuronal afferent impulses from the damaged tissue or the surgical site.
The immune response is the consequence of the interaction between T lymphocytes (LT), B lymphocytes (LB) and monocytes / macrophages. All these cells must communicate with each other and this is done by cytokines. In addition, cytokines are the main messenger of the immune system to the brain, so that it receives information from the immune system and responds to it. Cytokines are characterized by their pleiotropy and functional redundancy. They usually act on cells by binding to specific receptors. They can act locally or in cells further away from the site of production. Some functionally important cytokines are interleukins , interferons, or tumor necrosis factors.
The deficiency of the different types of cytokines or their receptors produces different pathologies. Its use in treatment is increasing. Currently there are therapies based on the use of GCSF, interferon alpha and interferon beta. Cytokines are not pre-elaborated in cellular compartments, but their synthesis begins after precise interactions and involves the transcription and synthesis of messenger RNA (mRNA). The same cytokine can be produced by multiple cell types, and each of them can act on different cells (pleiotropism).
Importance
They participate in such important processes as inflammation, the regulation of class I and class II MHC (Major Histocompatibility Complex) expression, immunosuppressive responses, the regulation of immunoglobulin isotype change, chemotaxis and effector function, normally cytotoxicity. Its function is immunoregulatory, being fundamental in communication and in the interactions established by the cells of the immune system with each other and with other cells. Cytokines direct the innate immune response and the specific immune response and are involved in inflammation and hematopoiesis . To do this, they activate macrophages , eosinophils , NK cells and neutrophils., induce the production of reactive oxygen and nitrogen species by macrophages and participate in hematopoietic processes.
In order to understand the importance of the study of cytokines by medical professionals related to anesthesia , surgery, trauma and critical medicine, they must be placed in the context of the responses made by the body to surgical, traumatic and / or infectious aggression .
Surgery
The surgery results in a wide variety of metabolic changes include hyperglycemia , loss of muscle mass, protein synthesis acute and increase in peripheral blood leukocyte. These changes originate in neuronal, somatic, and autonomic afferents, and in the release of cytokines from the site of tissue injury.
Although anesthetic techniques completely block neuronal inputs, as can be achieved in surgery of the lower limbs, organs of the pelvis, or the eye , neuroendocrine and immune responses can be delayed, but do not completely disappear.
The response to surgical stress is initiated by three fundamental factors:
- Psychological perception (limbic cortex), related to preoperative anxiety
- Loss of extracellular fluid (volume receptors)
- Tissue damage (stimulation of nociceptive pathways and release of cytokines)
In this review we will discuss the activation of the cytokine network and the acute phase response produced in surgery and trauma. Chronic cytokine secretion, for example in sepsis , should be the subject of another review.
Importance of cytokines in anesthesia and surgery
The immunosuppression observed after major surgery is the result, mainly, of T lymphocyte dysfunction, and is characterized by impaired synthesis of IL-2 and interferon gamma (INF-g). The inability to produce an adequate amount of IL-2 causes an incomplete proliferation of T helper lymphocytes in response to antigenic stimulation, and a deficiency in INF-g results in a deterioration of the antigen presentation capacity of monocytes.
Cytokines produced in response to surgery are involved in:
- Nonspecific inflammatory response
- Specific inflammatory response
- Hematopoiesis
- Tissue repair
Acute phase response
It is a response to tissue destruction that:
- Limits tissue damage
- Isolates and destroys infectious organisms
- It activates the repair processes necessary for the return of the damaged organ to its normal function.
In acute processes, as in uncomplicated surgery, it lasts a few days.
The acute phase response consists of:
- Alteration of temperature by direct action on the hypothalamus of some cytokines, generating a febrile response mediated through the production of postaglandin E2 (PGE2)
- Changes in the composition of plasma proteins (C-reactive protein, acid glycoprotein 1, 1 antitrypsin, 2 macroglobulin and serum amyloid protein)
- Increase in the number of granulocytes in the peripheral blood, initially as an increase in the release of bone marrow deposits and later by an increase in their production
- IL-1 and IL-6 stimulate ACTH secretion and consequently cortisol production. These increases exert a feedback effect on the cytokines, since they inhibit the expression of the genes producing cytokines.
The proteins of the acute phase (more than 30) are synthesized in the liver and are involved in the inflammatory process and tissue repair. Some are useful as indicators of the presence and magnitude of the inflammatory process, such as C-reactive protein.
Macrophages or monocytes are those that begin the acute phase response at the site of tissue damage, releasing a wide spectrum of mediators, of which IL-1 and TNF-a are initiators of the process, acting locally on stromal cells fibroblasts and endothelial cells and also at a distance, resulting in a second phase of cytokine release. In this phase, IL-6 is the most important and its primary effect is the hepatic induction of the production of proteins of the acute phase.
The most studied cytokines in relation to surgery are: IL-1, IL-2, IL-6, TNF-a and INF-g.
Families
From a functional point of view, there are five main families of cytokines:
- The family of inflammatory cytokines.
- The hematopoietic cytokine family.
- The family of cytokines produced by Th1 lymphocytes.
- The family of cytokines produced by Th2 lymphocytes.
- The chemokine family, with chemotactic effect.
They can also be grouped by families according to their three-dimensional structure:
- Hematopoietin- like structure family .
- Family of interferons .
- Superfamily of immunoglobulins .
- Family of TNF-like structure (Tumor Necrosis Factor: tumor necrosis factor).
Effects and action
Cytokines can act on many different cellular targets, with an action: a) Autocrine, binding to the same cell that secretes it b) Paracrine, acting on a nearby cell and, c) on some occasions, with an endocrine action, binding to cells distant.
In addition, the action of cytokines can be (Fig. A):
- Pleiotropic, Redundant
- Synergistic or Antagonist
Thus, there is considerable overlap and redundancy of effects between them.
Cytokines can exert their action:
- At the local level (autocrine action), activating receptors present in the same manufacturing cells
- At the level of nearby cell receptors (paracrine effect)
- On distant cells (endocrine effect), in the event that the concentrations released into the circulatory stream are very high.
The cellular response to cytokines is also slow (hours), as it requires the formation of mRNA and the subsequent synthesis of proteins. The action of cytokines is produced by binding to specific and very high affinity receptors, which is why very small amounts are required to trigger the biological effect.
Receptors are found on the cell surface and their expression is regulated through specific signals that can be generated by another or even the same cytokine, which makes it possible to amplify the positive signal or generate a negative feedback effect.
All receptors are glycoproteins made up of three regions:
- An extracellular domain, which provides the recognition region for the cytokine and determines the specificity
- An expanded transmembrane region along the lipid bilayer of the plasma membrane
- Intracellular domain responsible for generating the transduction signal
There are also soluble receptors that arise from the proteolytic cleavage of membrane receptors or by alternative splicing of mRNAs, whose main function would be to regulate the biological effects of cytokines.
General properties
Cytokines are secreted by various cells involved in the immune response in response to a stimulus, and act on target cells that express specific receptors for a given cytokine on their membrane. Binding of a cytokine to its membrane receptor transmits a signal into the cell that leads to changes in gene activation and expression . Furthermore, soluble receptors for the different cytokines have been detected in serum, the action of which is to contribute to the regulation of their activity.
Cytokines interact with each other:
- They can induce each other
- They can modulate the receiver of another
- May have synergistic, additive or antagonistic effects
The function of the receptors is to specifically recognize a cytokine and convert that interaction into a suitable intracellular signal.
The regulation of the action of cytokines is guaranteed by some mechanisms:
- Regulation of receptor expression.
- Due to the need for cell-cell interaction.
- Short duration of production (while the stimulus lasts) and short half-life of cytokines in blood and fluids.
- Binding of specific proteins to the receptor.
- Action of antagonistic cytokines.
Functional classification of cytokines
From a functional point of view, cytokines can be grouped into the following groups:
A. Mediators of adaptive immunity B. Mediators of innate immunity and inflammation C. Mediators of chemotaxis D. Mediators of hematopoiesis