Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interactions of the ligand/receptor pair LFA-1(CD11a/CD18) and ICAM-1(CD54) initiate and control the cell-cell interactions of leukocytes and interactions of leukocytes with parenchymal cells in all phases of the immune response. Induction of the intercellular adhesion molecule 1 (ICAM-1) on the surface of epidermal keratinocytes has been proposed as an important regulator of contact-dependent aspects of cutaneous inflammation. Ultraviolet radiation (UVR) also modifies cutaneous inflammation, producing both up- and down-regulation of contact hypersensitivity. We have found that UVR has a biphasic effect on the induction of keratinocyte CD54. Using immunofluorescence and FACS techniques to quantitate cell-surface CD54 staining, we have shown that UVR (100 mJ/cm2 of UVB) significantly (p less than 0.01) inhibits keratinocyte CD54 induction by gamma interferon 24 h after irradiation. However, at 48, 72, and 96 h after UVR (10 to 100 mJ/cm2), CD54 expression is significantly induced (p less than 0.01 to p less than 0.001) to levels even greater than are induced by gamma interferon (20 U/ml). In addition, at 48, 72, or 96 h following UVR (30-100 mJ/cm2), the gamma-interferon-induced CD54 expression on human keratinocytes is also strongly (p less than 0.05 to p less than 0.001) enhanced. In this cell-culture system, gamma interferon and TNF-alpha are both strong CD54 inducers and are synergistic, but GM-CSF, TFG-beta, and IL-1 have no direct CD54-inducing effects. Thus the effects of UVR on CD54 induction are biphasic, producing inhibition at 24 h and induction at 48, 72, and 96 h. This effect on CD54 may contribute to the biphasic effects of UVR on delayed hypersensitivity in vivo. The early inhibition of ICAM-1 by UVR may also contribute to the therapeutic effects of UVR. We also speculate that the late induction of ICAM-1 by UVR might be an important step in the induction of photosensitive diseases such as lupus erythematosus.
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PMID:Ultraviolet radiation can either suppress or induce expression of intercellular adhesion molecule 1 (ICAM-1) on the surface of cultured human keratinocytes. 197 76

Immunologic cytotoxicity is an important endpoint of the immune response to tumors, viral infected cells, grafted tissues, and exogenous microorganisms, and is also an important mechanism of disease, especially in autoimmunity. There are multiple mechanisms of immunologic cytotoxicity, but each has three major stages: leukocyte/target attachment, specific recognition, and target lysis following effector activation. Adhesion molecules present on leukocytes and potential targets appear to be involved in all three stages of cytotoxicity. A major factor in all types of cellular cytotoxicity is the interaction of LFA-1 on leukocytes and CAM-1 on targets. Modulation of ICAM-1 levels on target by the cytokines TFN-g, IL-1, and TNF-a is a major point of control of the susceptibility of targets to cytotoxicity by many different cytotoxic mechanisms. It also appears that modulation of the avidity of LFA/ICAM-1 binding is another important control point in modulating immunologic cytotoxicity. Cytokines also have important effects on immunologic cytotoxicity in ways other than adhesion molecule induction: effector priming to better respond to specific recognition signals, effector mobilization into tissue, and expansion of cytotoxic effector populations. ICAM-1 on the surface of epidermal keratinocytes and melanocytes is likely to greatly influence cytotoxic damage of these cells in diseases as photosensitive lupus erythematosus, lichen planus, erythema multiforme, and vitiligo. It has been found that the epidermal staining pattern for ICAM-1 in each of these diseases in distinctive and different in each disease. It is proposed that disease-specific induction of ICAM-1 by factors such as UVR and herpes-virus is an important determinant in triggering these skin diseases and in determining the pattern of disease.
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PMID:Cytokine modulation of adhesion molecules in the regulation of immunologic cytotoxicity of epidermal targets. 225 27

TNF and IL-1 are potent immunologic and inflammatory cytokines. We have previously reported increased levels of mRNA for TNF alpha and IL-1 beta in MRL-lpr mice with lupus nephritis. To determine whether the increased levels of TNF and IL-1 mRNA are a more general feature of mice with lupus nephritis we studied cytokine gene expression in female NZB x NZW F1 (NZB/W) mice by Northern blot analysis. Enhanced steady state levels of mRNA for TNF alpha and IL-1 beta, but not IL-1 alpha, were detected in the renal cortices of animals with lupus nephritis. To determine whether administration of TNF or IL-1 would accelerate renal injury and mortality, we injected murine rTNF alpha or rIL-1 alpha i.p. into female NZB/W or C3H/FeJ mice at two doses, 2.0 micrograms or 0.2 micrograms, three times weekly for 2 or 4 mo beginning at 2 or 4 mo of age. Administration of the lower dose of each cytokine accelerated renal disease and mortality rate when treatment was initiated at 4 mo of age. At the higher dose, neither cytokine promoted disease. Treatment administered from 2-4 mo of age did not accelerate renal disease. This observation suggests that in order to cause renal injury, these cytokines must interact with other pathologic features present in these animals after 4 mo of age. These findings support the hypothesis that TNF and IL-1 can contribute to nephritis in murine models of lupus. Taken together with previously published data, we propose that TNF and IL-1 have differential dose effects on renal disease. The dose of TNF and IL-1 and the stage of disease activity dictate the pathogenic action of these cytokines.
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PMID:Tumor necrosis factor and IL-1 in New Zealand Black/White mice. Enhanced gene expression and acceleration of renal injury. 258 2

The mononuclear-phagocyte system includes promonocytes and their precursors in the bone marrow, monocytes in circulation and macrophages in tissues. After maturation in the bone marrow newly formed monocytes enter the circulation and migrate into different tissues; the half-life of monocytes in the blood stream is approximately three days. Once in the tissue monocytes undergo transformation into tissue macrophages with functional properties that are characteristic for the environment in which they reside. Macrophages play a central role in the immune regulation by presenting antigen to T-lymphocytes; they participate in ingestion and killing of various invading microorganisms. In addition, macrophages synthesize a great number of substances involved in host defense and inflammation i.e. complement components, prostaglandins, IL-1, tumor necrosis factor-alpha and others. During infection, macrophages have the capacity to become "activated" by lymphokines and different bacterial products; "activated" macrophages have an increased tumoricidal and microbicidal activity against various microorganisms, synthesis and secretion of immune mediators is enhanced. Monocyte-macrophage dysfunctions have been described in various disorders: defective chemotaxis (corticosteroids, drug induced immunosuppression, AIDS, diabetes), defective phagocytosis (lupus erythematosus, deficiency of a membrane glycoprotein), microbicidal defect (chronic granulomatous disease), decreased cytotoxicity (Wiskott-Aldrich-Syndrome), deficiencies in the clearance of physiologic substrates in lysosomal diseases.
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PMID:[The monocyte-macrophage system in the human]. 267 85

Splenocytes of MRL/l mice, one of the murine lupus strains, were found to produce a factor(s) which potentiates antibody formation. This factor was produced by splenocytes of young MRL/l mice and cell-sorting experiments by flow cytometry indicated that Thy 1.2+ cells were producing the factor. The approximate molecular weight of the factor was found to be 35,000-45,000 daltons and its pI value was between 3.3 and 3.8. It was also demonstrated that this factor is distinct from interferons, interleukins (IL-1, IL-2, IL-3) and B cell differentiation factors.
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PMID:A factor potentiating antibody formation spontaneously produced by splenic T cells of MRL/MP-lpr/lpr mice. 349 82

The autoimmune syndrome in MRL/lpr mice resembles human lupus, both in its serologic and immunopathologic characteristics. The contribution of IL-1 to high-level Ig production in the MRL/lpr model is poorly understood. We investigated the effect of treating B-cell-enriched, or, B plus T cell suspensions derived from either pre-disease or diseased lupus-prone MRL/lpr mice with IL-1 beta or IL-1 receptor antagonist (IL-1Ra). Disparate patterns of IgG production by B cells and B plus T cells derived from diseased versus pre-diseased MRL/lpr mice was observed following treatment with IL-1 beta. Remarkably, IL-1 beta caused significant suppression in IgG production by B cells derived from diseased MRL/lpr mice as compared to B cells derived from pre-disease mice. In mix-and-match experiments with B plus T cells from pre-disease and diseased MRL/lpr mice, both T cell help and B cell hyperactivity, originating in diseased MRL/lpr mice were found to be important factors in high-level IgG production in diseased MRL/lpr mice. Furthermore, IL-1Ra treatment of B plus T cell co-cultures derived from diseased MRL/lpr mice was able to significantly suppress IgG production, whereas, IL-1Ra treatment of B plus T cell co-cultures derived from pre-disease MRL/lpr mice demonstrated virtually no suppression in IgG production. Collectively, these results indicate a potentially important but complex role for IL-1 in influencing high-level IgG production in MRL/lpr mice with established disease.
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PMID:Interleukin-1 contributes to high level IgG production in the murine MRL/lpr lupus model. 795 62

The MRL/lpr murine model resembles human lupus both in its serologic and immunopathologic features, and is characterized by high-level IgG and autoantibody production. The precise mechanisms for this B cell hyperactivity are poorly understood. This study explored the role of IL-1 in determining high-level IgG and autoantibody production in the MRL/lpr murine lupus model by blocking IL-1 activity with a recombinant IL-1 receptor antagonist (IL-1Ra). IgG and autoantibody production (anti-DNA ab and Id-H130 activity) by B cells derived from MRL/lpr mice was significantly suppressed by treating B cell cultures with IL-1Ra. In contrast, IgG and autoantibody production by B cells derived from young MRL/lpr, MLR/++, or normal C3H/HeJ mice showed virtually no suppression with IL-1Ra. Collectively, these findings indicate that IL-1 may be an important factor in determining the heightened production of IgG, anti-DNA, and id-H130 antibody production in lupus-prone MRL/lpr mice. Furthermore, heightened IL-1 activity appears to be influenced by both age and the presence of the lpr mutation.
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PMID:In vitro role of IL-1 in heightened IgG, anti-DNA, and nephritogenic idiotype production by B cells derived from the murine MRL/lpr lupus model. 806 53

The MRL/lpr model of SLE resembles human lupus in its various immunopathologic characteristics including the presence of high-level IgG and anti-DNA antibody production and multisystem organ involvement (nephritis, arthritis, and vasculitis). Our previous studies have shown that IL-1 overactivity in B cells plays a potentially important role in driving IgG and autoantibody production. However, the underlying mechanisms determining IL-1 overactivity are poorly understood. We studied IL-1 beta gene expression and transcriptional rates in B cells derived from old and young MRL/lpr, MRL/+ +, and non-autoimmune control mice using semi-quantitative RT-PCR and the nuclear run-on assay. RT-PCR demonstrated increased steady-state IL-1 beta gene expression in B cells derived from old MRL/lpr mice as compared to either young MRL/lpr or control mice. Furthermore, IL-1 beta gene expression in B cells was associated with the presence of the lpr mutation because heightened IL-1 beta message was observed in RNA obtained from MRL/lpr but not MRL/+ + B cells. IL-1 beta transcriptional rates measured by the nuclear run-on assay were very similar in B cells from old and young MRL/lpr and control mice. These observations suggest that IL-1 overactivity in B cells obtained from old diseased MRL/lpr results from heightened IL-1 beta message, is associated with the presence of the lpr mutation, and is likely to reflect post-transcriptional stabilization of IL-1 beta mRNA.
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PMID:IL-1 beta gene expression in B cells derived from the murine MRL/lpr model of lupus. 898 20

In systemic lupus erythematosus (SLE) is a disease characterized by B cell hyperactivity, autoantibody production and immune complex deposition in vital organs. To explain the mechanisms responsible for immune dysregulation in SLE cytokines have received increasing attention. This review has discussed a number of cytokines which appear to be involved in lupus pathogenesis. Recent studies have shown that disease activity and the main symptoms of SLE are associated with increasing serum levels of cytokines such as interleukin-(IL)-1, IL-2, IL-6, interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (THF-alpha). Constitutive expression and in vitro induction of specific cytokines are also aberrant in SLE. The presence of IL-1, IL-6 and IFN-gamma in involved kidneys suggests that they have local pathogenic effects. Moreover IFN-gamma, IL-6 and IL-1 modulate spontaneous IgG production by SLE mononuclear cells. During the next several years, the exact role of these cytokine in the pathogenesis of lupus become more fully elucidated.
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PMID:[Cytokines in systemic lupus erythematosus]. 899 65

We investigated whether macrophages (Mphi) from young, lupus-prone MRL+/+ and NZB/W F1 mice expressed common defects in immunoregulatory cytokine production. Endotoxin-activated Mphi from both strains, obtained well before disease signs, had a markedly reduced capacity to maintain IL-1 production compared with Mphi from normal strains (BALB/c, A/J, and C57BL/6). Mphi from lupus-prone mice showed similar defects in IL-6 and TNF-alpha production, which preceded the IL-1 defect. In fact, defective TNF-alpha production appeared to be responsible for aberrant expression of the other cytokines because this defect was the first to be expressed, and treatment with exogenous TNF-alpha reduced the extent of defective IL-1 and IL-6. These "proinflammatory" cytokine defects appeared to be selective because the anti-inflammatory cytokine IL-10 was not expressed aberrantly in the lupus-prone strains. For this reason, and because anti-IL-10 mAb treatment did not correct defective proinflammatory cytokine production, IL-10 did not appear to be responsible for these defects. IFN-gamma was able to normalize TNF-alpha production in Mphi from lupus-prone mice, demonstrating a stimulus-specific induction of the proinflammatory defects. These studies also revealed that Mphi from the three normal strains studied here maintain a precise inverse relationship between levels of TNF-alpha and IL-10, a relationship not seen in Mphi from lupus-prone strains. These findings reveal shared elements of cytokine dysregulation in the two principal animal models of multigenic lupus, and suggest that the study of Mphi (and perhaps other cells of the innate immune system) may provide valuable insights into intrinsic functional defects associated with systemic autoimmunity.
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PMID:Aberrant cytokine expression and autocrine regulation characterize macrophages from young MRL+/+ and NZB/W F1 lupus-prone mice. 954 4


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