الفهرس 
- ¬Structure and Dynamics of KeratinocytesOnly 14 pages are availabe for public view
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Abstract
Keratinocyte is the principal cell population in the epidermis that undergo a tightly regulated differentiation process, and give rise to several morphologically distinguishable layers as they move outwards. Its cytoplasm contains intermediate filaments composed of a fibrous protein (Keratin) that participate in the formation of its cytoskeleton.Keratinocytes are interconnected by specialized structures termed desmosomes. Also they express many markers that are specific for them like keratins, profilaggrin and desmosomal proteins.
The skin is the largest organ in the body and is the principal physical barrier between the body and the external environment. In addition, the skin is an active participant in host defense, with the ability to generate local immune and inflammatory reactions. Many foreign antigens gain entry into the body via the skin, so many immune responses are initiated in this tissue.
Keratinocyte is considered as one of the components of the cutaneous immune system. It produces a number of cytokincs when damaged, or actively secretes them when stimulated. These cytokines augment inflammation. Keratino-cytes can bring inflammatory cells, including lymphocytes, into the viable epidermis.
Epidermal keratinocytes have constitutive phagocytic capabilities. Keratinocytes can engulf and degrade low molecular mass proteins such as fibrin fragments during wound healing. Moreover, pigment (melanosome) transfer from melanocytcs to keratinocytes is mediated by keratinocyte phagacytosis. Protease activated receptor-2 is expressed in numerous cell types, including keratinocytes. It induces keratinocytes to be actively involved in pathogen phagocytosis.
A number of factors are capable of triggering immune responses in keratinocytes such as ultraviolet radiation, contact allergens/irritants, trauma and wound repair.Ultraviolet radiation (UV) is an important environmental factor that modulates kerationcyte functions in many ways, and is responsible for carcinogenesis, photoageing, inflammation or immunosuppression. Ultraviolet radiation results in deoxyribonucleic acid (DNA) damage, and causes the induction of cytokines, growth factors, proteases or matrix metalloproteinases, which regulate keratinocyte function.
After activation by trigger factors, several immune mediators are produced by keratinocytes such as cytokines and chemokines. For examples TNF-α, GM–CSF, IL-15 and CCL5/RANTES are induced by keratinocytes in pathological condition, while IL-1α, IL-18 and CCL27/CTACK are constitutively produced by keratinocytes.
Keratinocytes have an important role in the pathogenesis of chronic inflammatory skin diseases such as psoriasis, ACD and atopic dermatitis through production of immune mediator.
The role of keratinocytes during (ACD) has been examined, more with respect to cytokines secretion and tolerance induction, and less as a source of antigenic proteins to which chemical haptens can conjugate. During the elicitation phase of ACD, after the hapten-induced activation, keratino-cytes are exposed to a cytokine milieu established primarily by memory hapten-specific T cells, which accumulate in the skin at both dermal and epidermal levels. Among hapten-specific T lymphocytes, IFN-γ -secreting type 1 T clones predominate.
During the amplification phase of ACD, cytokine-activated keratinocytes become also an important source of chemotactic factors that direct the recruitment of specific leukocyte subpopulations. The expression of CCL5/RANTES, CXCL10/IP-10 and CXCL9/Mig begin at 12 hours after hapten application and reach the maximum at 72 hours, paralleling the strong infiltration of lymphocytes. Some hapten such as nickel induce a direct inflammatory activation of keratinocytes resulting in the expression of cytokines, chemokines and adhesion molecules
Hyperproliferation of keratinocytes is a hallmark of psoriatic lesions. The stem cell population of β1+β4+ integrin cells is responsible for hyperproliferation with accelerated terminal differentiation.
In psoriatic lesions, under the influence of IFN- γ and TNF-α, keratinocytes produce cytokines, chemokines and adhesion molecules, which further amplify the inflammatory response. keratinocyte production of chemokines may contribute relevantly to the establishment of the inflammatory infiltrate. Specifically, CXCL8/IL-8 and related chemokines are responsible for the intra-epidermal collection of neutrophils. CCL2/MCP-I, CCL5/RANTES, CXCL10/IP-10 and other CXCR3 ligands predominantly attract monocytes and ThI cells ,whereas CCL20/MIP-3α recruits immature Langerhans cells, dendritic cells and CLA T cells.
The signal transduction initiated by IFN-γ and TNF-α involves principally a co-operation between STAT-1 and NFkB transcription factors. AP-1 is known to be less important in the signaling elicited by these cytokines in contrast to AD.
Several biologic attributes of keratinocyte relevant for AD are: intrinsic defects in barrier function, production of inflammatory mediators that promote or maintain allergic inflammation, keratinocyte apoptosis, effects of staphylococcal toxins on keratinocytes and potential consequences of the expression of co-signaling molecules (e.g. B7 family members) and receptors important for innate immune responses (e.g. Toll receptors).
Itch sensation that frequently leads to scratching and epithelial barrier defect (denoted by widening of the intercellular spaces), which becomes more dramatic in response to the trauma of scratching and dermal inflammation. This provides a portal of entry for allergens/irritants and microbes, resulting in their immunologic processing and recognition. Staph is thought to bind to the TLR2 receptor, found on both keratinocytes and antigen presuming cells (e.g. LC).The innate signals induced by the trauma of scratching and microbial invasion result in the release of IL-1 and TNF. These cytokines are probably responsible for the initiation of the inflammatory response; activating endothelial cells to express adhesion molecules, induction of the immunomodulatory cytokines TSLP, GM-CSF, TARC, CTACK, RANTES and, in conjunction with Th2 cylokines, the induction of MCP-4 and eotaxin by keratinocytes. These downstream cytokines are important in maturation of antigen presenting cells, and the recruitment of relevant leukocyte subtypes (CLA+ T helper cells, eosinophils, and monocytes).