Keratinocytes as initiators of inflammation

Abstract

Environmental stimuli responsible for inducing cutaneous inflammation include contact allergens and ultraviolet light. We postulate that these diverse stimuli trigger a cutaneous inflammatory response by directly inducing epidermal keratinocytes to elaborate specific pro-inflammatory cytokines and adhesion molecules. The consequences are activation of dermal microvascular endothelial cells and selective accumulation of specific mononuclear cells in the dermis and epidermis. Thus, keratinocytes may act as "signal transducers", capable of converting exogenous stimuli into the production of cytokines, adhesion molecules, and chemotactic factors (acting in an autocrine and paracrine fashion) responsible for initiation of "antigen-independent" cutaneous inflammation. The initiation phase may facilitate or promote an amplification phase with additional production of tumour-necrosis factor alpha and interferon gamma via an "antigen-dependent" pathway, and keratinocyte/T cell/antigen-presenting dendritic cellular associations. The direct activation of keratinocytes, with their ability to produce the complete repertoire of pro-inflammatory cytokines, can profoundly influence endogenous and recruited immunocompetent cells, thereby providing the critical trigger responsible for the swift and clinically dramatic alterations that occur following contact between the epidermis and a host of "noxious" agents.

Identification of macrophage migration inhibitory factor (MIF) in human skin and its immunohistochemical localization

“…To date, several cytokines, including IL-10t, TNF-c4 IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), and transforming growth factor-t~ (TGF-ct), have been found in epidermal keratinocytes [1]; however, only IL-lc~ could be shown to be stored in normal skin in a biologically active form [10]. Cytokines released from keratinocytes can be induced by environmental stimuli such as trauma, bacterial toxins and ultraviolet light.…”

“…It has been reported that various cytokines play important roles in homeostasis of normal skin and in its pathology [1]. Diverse stimuli trigger a cutaneous inflammatory response by activating specific pro-inflammatory cytokines, such as tumor necrosis factor-~ (TNF-c0 and interleukin-1 (IL-1); however, the detailed interrelation of the cytokines to the pathophysiological mechanism has not been well elucidated.…”

Contact allergy, irritancy and ‘danger’

“…This may be because the threshold for irritancy of the hapten that is required to initiate the inflammatory response is much lower in vitro than in vivo. Haptens may act first on keratinocytes and then subsequent cytokine-induced responses will elicit the contact hypersensitivity (CHS) response (34). The cytokines involved may include TNFa and Il-1, as intradermal injections of these give a CHS-like response (33).…”

“…Nickel, for example, can cause nonspecific cytokine release from keratinocytes (34). Most contact allergens under patch test conditions have the capability of producing irritant reactions.…”

Role of cytokines in epidermal Langerhans cell migration

“…Resting KC synthesize and secrete low levels of cytokines, however, stimuli including allergens, irritants, ultraviolet light, bacterial products such as endotoxin, and physical trauma induce KC to produce significant amounts of cytokines. KC effectively function as basic signal transducers, capable of converting exogenous stimuli into host homeostatic responses [21]. LC also produce certain cytokines such as IL-1␤, IL-6, IL-12, and IL-18, which play important roles in initiation and modulation of cutaneous immune responses [22][23][24][25][26][27][28] (Table 1).…”