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The innate immune system is an ancient and diverse collection of defenses, including the recognition of pathogens through the use of germline-encoded pathogen receptors. The adaptive immune system, encompassing T and B cell responses, is a more recent development that utilizes somatically recombined antigen receptor genes to recognize virtually any antigen. The adaptive immune system has the advantage of flexibility and immunologic memory but it is completely dependent upon elements of the innate immune system for the initiation and direction of responses. Appropriate innate and acquired immune system interactions lead to highly efficient recognition and clearance of pathogens, but maladaptive interactions between these two systems can result in harmful immunologic responses including allergy, autoimmunity, and allograft rejection. more...

The proinflammatory cytokine interleukin-12, a p35/p40 heterodimer, is produced by resident cells in skin and has been implicated as a pathogenetic factor in T-cell-mediated skin diseases. Secretion of heterodimeric interleukin-12 is always accompanied by production of p40 monomer and p40/p40 homodimer. To investigate the possible in vivo role of p40 per se, we generated mice that constitutively express monomeric and homodimeric p40 in basal keratinocytes. These mice spontaneously developed an eczematous skin disease that was characterized by hyperkeratosis, focal epidermal spongiosis, and a mixed inflammatory infiltrate composed of T cells (CD4+), macrophages, eosinophils, mast cells, and few neutrophils. Fluorescence-activated cell sorter analysis of transgenic epidermal cell suspensions revealed induction of major histocompatibility complex class II molecules on keratinocytes and a 2-3-fold increase in the content of Langerhans cells. Cytokines produced by these activated epidermal cells include interleukin-1alpha and tumor necrosis factor alpha. The skin disease in K14/p40 mice was similar to that of littermate mice that received injections of interleukin-12, suggesting overlapping in vivo functional properties. As induction of interferon-gamma is a major function of interleukin-12, we tested the in vitro ability of transgenic p40 to induce interferon-gamma. In contrast to interleukin-12, transgenic p40 did not stimulate interferon-gamma secretion by cultured splenocytes. We conclude that transgenic p40 and interleukin-12 are equally capable of initiating cutaneous inflammation. Despite these in vivo similarities, there is a clear functional difference between interleukin-12 and transgenic p40 in vitro, suggesting that interferon-gamma is not a major factor contributing to interleukin-12-like activities of transgenic p40. more...

As our primary interface with the environment, the skin is constantly subjected to injury and invasion by pathogens. The fundamental force driving the evolution of the immune system has been the need to protect the host against overwhelming infection. The ability of T and B cells to recombine antigen receptor genes during development provides an efficient, flexible, and powerful immune system with nearly unlimited specificity for antigen. The capacity to expand subsets of antigen-specific lymphocytes that become activated by environmental antigens (memory response) is termed "acquired" immunity. Immunologic memory, although a fundamental aspect of mammalian biology, is a relatively recent evolutionary event that permits organisms to live for years to decades. "Innate" immunity, mediated by genes that remain in germ line conformation and encode for proteins that recognize conserved structural patterns on microorganisms, is a much more ancient system of host defense. Defensins and other antimicrobial peptides, complement and opsonins, and endocytic receptors are all considered components of the innate immune system. None of these, however, are signal-transducing receptors. Most recently, a large family of cell surface receptors that mediate signaling through the NF-kappaB transcription factor has been identified. This family of proteins shares striking homology with plant and Drosophila genes that mediate innate immunity. In mammals, this family includes the type I interleukin-1 receptor, the interleukin-18 receptor, and a growing family of Toll-like receptors, two of which were recently identified as signal-transducing receptors for bacterial endotoxin. In this review, we discuss how interleukin-1 links the innate and acquired immune systems to provide synergistic host defense activities in skin. more...

Human immunodeficiency virus (HIV) is known to infect Langerhans cells, but controversy still exists about the occurrence of HIV-infected Langerhans cells in the skin of HIV-infected individuals and about the density of epidermal Langerhans cells during the course of HIV disease. In this study, epidermal Langerhans cell population densities were analyzed quantitatively in serial biopsies from two burn patients acquired over an 11-y period following infection with HIV from transfusions received during their acute treatment. At each biopsy time point, the density of epidermal Langerhans cells and the proportion that were infected with HIV were analyzed by immunostaining. In both patients, skin grafts were slow to repopulate with Langerhans cells and did not attain normal Langerhans cell densities until about 2 y after grafting. Thereafter, Langerhans cell densities remained within normal limits with the exception of six biopsies at random times that showed a supernormal number of epidermal Langerhans cells. HIV-infected Langerhans cells were first detected at about 2 y post-infection and comprised about one-third of the Langerhans cell population. At subsequent times, HIV p24-stained Langerhans cells were identified in most biopsies and typically constituted about one third to one half of the total Langerhans cell population. The findings show that HIV-bearing Langerhans cells constitute a significant proportion of the epidermal Langerhans cell population over long periods of asymptomatic disease but are unevenly distributed throughout the skin. Normal population densities of epidermal Langerhans cells are maintained for years, although transient increases may occur randomly. more...

Chemokines are thought to play a central role in the recruitment and activation of leukocytes during inflammatory responses. Monocyte chemoattractant protein 1 (MCP-1) is a chemokine of the C-C or beta family that is chemotactic in vitro for monocytes, T cells, and basophils. Its excessive production by keratinocytes has been implicated in psoriasis and other skin diseases. To test the in vivo role of MCP-1 in inflammatory skin disease, we undertook the generation of transgenic mice that express murine MCP-1 in the basal layer of epidermis. Despite production of high levels of functional MCP-1 by basal keratinocytes, documented in vivo and in vitro, these mice did not exhibit spontaneous cutaneous inflammation or any other discernible skin pathology. In contrast, elicited inflammation in the skin of these mice differed qualitatively and quantitatively from that observed in non-transgenic controls. Contact hypersensitivity challenge responses in transgenic animals were characterized by an exaggerated lichenoid infiltration of monocytes and T cells. Additional phenotypic characterization of the normal appearing skin in these mice showed that the only spontaneous change was a dramatic increase and redistribution of CD45+, I-A+ cells that assumed a dendritic morphology in situ, including a subset that expressed markers characteristic of Langerhans cells. Taken together, these data indicate that tissue-specific expression of MCP-1 alone is not sufficient to induce an inflammatory response, though its presence can modify inflammatory and immune events initiated by exogenous stimuli. The recruitment of dendritic and Langerhans cells in the absence of inflammation is a previously unknown consequence of cutaneous MCP-1 production in vivo. more...

Since the discovery that epidermal cell-derived thymocyte-activating factor was identical to interleukin (IL)-1 alpha and -beta in 1986, these molecules have been implicated in the pathogenesis of skin diseases. In 1995, it has become clear that a group of gene products function to regulate the activity of IL-1. IL-1 alpha and mature 17-kD IL-1 beta (cleaved from precursor by IL-1 beta-converting enzyme) bind to the type 1 IL-1 receptor to transduce a signal. This process can be antagonized at the level of the receptor by two distinct forms of the IL-1 receptor antagonist, which bind to the type I receptor but do not transduce a signal. The process can also be antagonized at the level of the ligand by either cell-bound or soluble type 2 IL-1 receptor. This type 2 IL-1 receptor binds ligand but does not transduce a signal. Keratinocytes can make each of these variables in vitro, and the balance between agonists and antagonists dictates the biologic outcome of a putative IL-1-mediated event. Transgenic mice that overexpress each of these factors individually in epidermis will be useful for enhancing our understanding of the cutaneous biology of IL-1. more...

Keratinocytes, fibroblasts, endothelial cells, and other sessile cells resident to human skin can be induced in vitro to synthesize and secrete cytokine molecules. Cytokines are small protein molecules produced upon injury or cellular activation which influence immune and inflammatory events; as such, they have been best understood previously as products of leukocytes. The appreciation that cultured non-bone marrow-derived cells from skin could produce cytokines capable of initiating an inflammatory response or facilitating an immune response has led to speculation that cells resident to skin may be less passive participants in such phenomena than previously thought. Using as a model the cultured keratinocyte, which produces both interleukin-1 alpha and beta and an interleukin-1 receptor, models of autocrine and paracrine activation of this cell have been constructed. Such "activated keratinocytes," or by analogy other activated resident skin cells, produce a spectrum of cytokines in vitro which could potentially influence leukocyte adhesion to endothelium, direction migration of leukocytes towards the activated cell (presumably an inflammatory nidus), and activation of leukocyte functions in situ. The putative role of regulation of cytokine and cytokine-receptor regulation in mediating the activation of such cells (and thus, presumably, local inflammation) is discussed. An important aspect of this hypothetical model is that in the absence of activation (which characterizes normal uninflamed skin), cytokine production and its consequences do not occur. The conclusion reached is that based on in vitro data it is plausible to guess that local inflammatory or immune responses can be both initiated and facilitated by locally produced cytokines. more...

The biological effects of the two interleukin-1s on cells of connective tissue origin are mediated by specific cell-surface receptors. Molecular cloning studies have revealed that these receptors are identical in protein sequence to the IL-1 receptors on cells of the T-lymphocyte lineage. The functional interleukin-1 receptor on T-cells and fibroblasts is composed of a single polypeptide chain that binds both IL-1 alpha and IL-1 beta. The single chain appears to be all that is required to transduce a signal to cells. While the nature of the signal is unknown, the structure of the receptor is inconsistent with its possessing any protein tyrosine kinase activity. It is therefore not surprising that the mitogenic activity of IL-1 for fibroblasts is mediated by IL-1 induction of PDGF-A gene transcription. Finally, IL-1 is known to modulate fibroblast-matrix interactions in several ways. It is interesting therefore, that the majority of the IL-1 receptors on cultured fibroblasts are clustered into focal adhesions. more...

Keratinocyte derived T-cell growth factor was initially described as a product of cultured neonatal keratinocytes and keratinocyte cell lines that induced the proliferation of HT-2 cells, a murine T-cell line that responds to IL-2 and IL-4 by incorporating 3H-Thymidine. Subsequently, KTGF has been purified to high specific activity and found to be distinct from IL-2 and IL-4 by a variety of biochemical, immunologic, and immunochemical criteria. Because it was found that certain HT-2 cell lines also proliferated in response to GM-CSF, the present study asked whether KTGF was related to GM-CSF. In this study, we demonstrate that antibodies to recombinant murine GM-CSF completely neutralize the capacity of KTGF to induce HT-2 proliferation without interfering with IL-2 or IL-4 induced HT-2 proliferation. Furthermore, poly-A+ RNA homologous to murine GM-CSF cDNA as judged by S1 nuclease analysis was detected in Pam 212 cells, and protein serologically homologous to GM-CSF was found in Pam 212 conditioned medium. We conclude that KTGF is identical to GM-CSF. The T-cell activating properties of GM-CSF require further exploration. more...

Epidermal thymocyte activating factor (ETAF) is spontaneously released into the media by PAM 212 and A 431 cell lines and cultured normal human keratinocytes. ETAF from all 3 cell types can substitute for interleukin 1 (IL-1) in the augmentation of proliferation of a helper T-cell clone (D10.G4.1) induced by mitogen. Hydrocortisone (HC) substantially reduces the release of ETAF by these keratinocytes and, further, appears to induce the release of an inhibitor of lymphocyte activating factor activity of IL-1. Irradiation with UVC causes increased ETAF release into the media. Hydrocortisone abrogates this effect. Thus HC reduces both constitutive and elicited release of ETAF. ETAF plays a major role in inflammation; the ability of HC to block ETAF release by keratinocytes may account for the anti-inflammatory effect of glucocorticosteroids on the skin. more...

This study describes the association between secreted keratinocyte interleukin 1 (IL-1) and its presence on the keratinocyte cell surface. These properties were studied in normal and transformed human keratinocytes as well as in transformed murine keratinocytes. We will present evidence that the secretion of IL-1 by human and murine keratinocytes is associated with the presence of IL-1 on the keratinocyte membrane. In addition, although transformed murine keratinocytes secrete other cytokines, namely keratinocyte T-cell growth factor (KTGF) and IL-3, no KTGF or IL-3 activity can be demonstrated on the cell surface. more...