Immune and inflammatory processes in cutaneous tissues. Mechanisms and speculations.

Abstract

PerspectivesEpithelial tissues in general (and skin in particular) define boundaries between inside and outside, host and environment. Mammalian skin and its appendages are poised at the critical interface between the delicately balanced internal milieu ofthe host and the mercurial forces of the outside world. Human skin diseases characterized by histopathologically distinct patterns of infiltration by T cells, B cells, monocytes, and granulocytes (referred to collectively as leukocytes) number quite literally in the hundreds. To state that the pathophysiologic mechanisms involved in the evolution of such unique inflammatory infiltrates are poorly understood is to euphamize; yet, recent advances have begun to allow for the construction of hypothetical paradigms that address the issue of mechanism in cutaneous immune and inflammatory processes.While skin was once considered the inert canvas upon which immune and inflammatory processes were painted by the bone marrow-derived host defense system, it is becoming apparent that resident sessile cells of skin are perhaps no less important in the generation ofa cutaneous immune or inflammatory response. This contention is based upon two broad classes of observation. The first is that nonhematopoieticallyderived cells resident to skin (including dermal fibroblasts, endothelial cells, and epidermal keratinocytes and melanocytes) can produce various cytokines upon appropriate stimulation (reviewed in reference 1) that affect decisively the behavior and function of lymphocytes, granulocytes, and monocytes. The second class of observation is that several of these cytokines influence the expression of adhesion molecules on endothelial and epithelial cells (1, 2). Taken to their logical conclusions, these observations suggest that nonhematopoietically-derived cells of skin, by virtue of their potential for cytokine production, have the indirect capacity to trap appropriate classes of leukocytes within microvasculature at precise anatomical sites, guide them through vessel walls and through dermal tissue along chemotactic gradients, and then activate them in situ. This article will review some of the evidence for this special immunocompetence of the skin, especially with regard to newer observations relating to cytokine production. Cytokines in cutaneous tissuesIt is axiomatic that cells ofdistinct lineages must communicate during the successful localization and evolution of an inflammatory response, and cytokines comprise an important part of

Keratinocyte expression of the type 2 interleukin 1 receptor mediates local and specific inhibition of interleukin 1-mediated inflammation

“…Cytokines, including IL-1␣ stored in keratinocytes, are emergency molecules, designed to be active for limited periods of time in local microenvironments such as skin (33)(34)(35). We have postulated previously that keratinocyte expression of IL-1R2 could be a mechanism by which IL-1-mediated cutaneous responses are negatively regulated (10,11).…”

“…issue (33). We successfully generated two independent lines of transgenic mice that overexpress IL-1R2 in basal epidermis.…”

Epidermal expression of intercellular adhesion molecule 1 is not a primary inducer of cutaneous inflammation in transgenic mice.

“…Elevated levels of keratinocyte ICAM-1 expression were found to be spatially and temporally associated with leukocytic infiltration of epidermis in spontaneously occurring inflammatory diseases of skin (7,9) and experimentally induced cutaneous inflammation (10). In the poison-ivy dermatitis model, ICAM-1 expression was reported to precede epidermal infiltration with T lymphocytes (10) (25). To migrate from the bloodstream toward the epidermis and physically interact with keratinocytes, leukocytes must successfully negotiate multiple and distinct obstacles.…”

IL-4 regulation of IL-6 production involves Rac/Cdc42- and p38 MAPK-dependent pathways in keratinocytes

“…Epidermal keratinocytes which represent a major constituent of the skin, produce various cytokines such as transforming growth factor (TGF) a, tumor necrosis factor (TNF) a, interferon g, granulocyte-macrophage colony-stimulating factor (GMCSF), interleukin (IL)-1, IL-6 and IL-8 (Kupper, 1990). Of these, IL-6 is interesting in that it is a multifunctional cytokine involved in immune and in¯ammatory responses, which stimulates proliferation of both epidermal cells and lymphocytes (Kishimoto, 1989;Krueger et al, 1991;Turksen et al, 1992).…”