Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the influence of age on B-cell responsiveness. The present study showed that the B-cell mitogen, lipopolysaccharide (LPS), similarly stimulated the proliferation of purified B lymphocytes obtained from either young mice (3 months) or old mice (24 months). In contrast, expression of the differentiation marker, alkaline phosphatase (ALP), was about fourfold higher in young mice than in older mice upon stimulation with LPS or with dextran sulfate (DXS) and interleukin-5 (IL-5). The occurrence of apoptosis during aging was then studied: unexpectedly, spontaneous cell death was double in B lymphocytes from young mice compared to older animals. Stimulation with DXS with or without IL-5 rescued B lymphocytes from cell death in young mice but protection decreased with aging, and no longer occurred in 24-month-old mice B cells. Meanwhile, the protective activity conferred by IL-4 was maintained at similar levels throughout aging. However, B cells from old mice were more responsive to apoptosis induction with cycloheximide, dibutyryl cAMP and dexamethasone. Together, the present results indicate an age-associated alteration in apoptosis and activation of B lymphocytes which could contribute to the age-related decline of the immune response.
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PMID:Age-associated modulation of apoptosis and activation in murine B lymphocytes. 972 4

Linear IgA bullous dermatosis (LAD) is an acquired, heterogeneous, subepidermal blistering disease characterized by linear IgA deposits at the dermoepidermal basement membrane zone (BMZ), often with circulating IgA antibodies to the BMZ. The pathogenetic mechanism, possibly related to the immunophenotype of infiltrating cells, as well as the potential role of cytokines in determining bullous lesions, have not yet been elucidated. An immunohistochemical study was performed with a large panel of monoclonal antibodies [to CD3, CD4, CD8, CD25, CD1a, CD30, CD54, CD50, endothelial leucocyte adhesion molecule-1, vascular cell adhesion molecule-1, myeloperoxidase (MPO), eosinophil cationic protein EG1 and EG2, tryptase, HLA-DR, human interleukin (IL)-3, human IL-5, human IL-8, human IL-4, tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma and granulocyte/macrophage colony-stimulating factor] using the alkaline phosphatase-antialkaline phosphatase procedure on lesional and perilesional skin of nine patients (one male, eight female; age range 8 months-80 years) with clinical, histological and immunofluorescent proven LAD. The predominant infiltrating cells, distributed mostly inside and below the bullae, were neutrophils and eosinophils which showed intense activation (MPO +, EG1 +, EG2 +). The lymphocytic infiltrate, consisting principally of CD4 +, HLA-DR + and CD30 + T cells, had a predominantly perivascular distribution. Proinflammatory cytokines, such as TNF-alpha and IFN-gamma, showed a moderate focal expression on the dermal perivascular sites; IL-8 was found to have a particularly intense staining on all the epidermal cell layers and at perivascular and vascular sites. Other cytokines, such as IL-4 and IL-5, showed a prevalent intracytoplasmic staining on some cells of the dermal infiltrate (probably mastocytes and lymphocytes), and at the dermal-epidermal separation sites there was also an intense scattered distribution of IL-5. The specific tissue lesions of LAD may be the consequence of the IgA deposits at the BMZ and also of the release of these cytokines together with tissue damage enzymes derived from neutrophils or eosinophils.
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PMID:The role of lymphocytes, granulocytes, mast cells and their related cytokines in lesional skin of linear IgA bullous dermatosis. 1035 73

Integral immunohistochemical analysis of immune responses in frozen sections requires that, in addition to constitutively expressed membrane CD markers, less stable determinants can be reliably visualized. Therefore, we compared the commonly used acetone fixation method with pararosaniline fixation for six determinant categories. These categories included selected constitutively expressed markers, inducible co-stimulatory molecules, pro- and anti-inflammatory cytokines (including the novel cytokine IL-18, also known as IGIF and IL-1gamma), antigen-specific antibody in plasma cells, bacterial peptidoglycan, and lysosomal acid phosphatase activity. Human spleen and mouse spleen activated by agonistic anti-CD40 antibody or TNP-Ficoll immunization were analyzed in parallel with brain tissue from multiple sclerosis (MS) patients and marmoset monkeys with experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Fixation with pararosaniline resulted in better morphology of all tissues and inhibited endogenous alkaline phosphatase activity in brain tissue. Most determinants could be reliably detected. Staining sensitivity and intensity were markedly increased for selected determinant-tissue combinations, e.g., for IL-4 in human spleen and CD40 in human and mouse spleen. These data show that pararosaniline is a useful alternative to acetone, resulting in superior morphology and specific staining for selected determinant-tissue combinations. This provides additional flexibility for in situ analysis of immune reactivity.
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PMID:Pararosaniline fixation for detection of co-stimulatory molecules, cytokines, and specific antibody. 1065 90

The interaction between CD40 on B cells and CD40 ligand (CD40L) on activated T cells is important for B-cell differentiation in T-cell-dependent humoral responses. We have extended our previous murine studies of CD40-CD40L in adenoviral vector-mediated immune responses to rhesus monkeys. Primary immune responses to adenoviral vectors and the ability to readminister vector were studied in rhesus monkeys in the presence or absence of a transient treatment with a humanized anti-CD40 ligand antibody (hu5C8). Adult animals were treated with hu5C8 at the time vector was instilled into the lung. Immunological analyses demonstrated suppression of adenovirus-induced lymphoproliferation and cytokine responses (interleukin-2 [IL-2], gamma interferon, IL-4, and IL-10) in hu5C8-treated animals. Animals treated with hu5C8 secreted adenovirus-specific immunoglobulin M (IgM) levels comparable to control animals, but did not secrete IgA or develop neutralizing antibodies; consequently, the animals could be readministered with adenovirus vector expressing alkaline phosphatase. A second study was designed to examine the long-term effects on immune functions of a short course of hu5C8. Acute hu5C8 treatment resulted in significant and prolonged inhibition of the adenovirus-specific humoral response well beyond the time hu5C8 effects were no longer significant. These studies demonstrate the potential of hu5C8 as an immunomodulatory regimen to enable administration of adenoviral vectors, and they advocate testing this model in humans.
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PMID:Readministration of adenovirus vector in nonhuman primate lungs by blockade of CD40-CD40 ligand interactions. 1070 52

Active vitamin D metabolites are not only involved in the regulation of bone metabolism but exerts immunomodulatory effects important in the regulation of inflammatory processes. The purpose of the present study was to evaluate the effects of a short-time treatment with 1 alpha-hydroxycholecalciferol on both disease activity and bone metabolism in patients with rheumatoid arthritis (RA). The effects of an adjuvant therapy with 1 microgram 1 alpha-hydroxycholecalciferol over eight weeks on conventional parameters of disease activity (Ritchie index, duration of morning stiffness, C-reactive protein, ESR), serum levels of cytokines and soluble cytokine receptors (TNF-alpha, IL-6, IL-4, sIL-2R, sIL-6R) and parameters of bone metabolism (bone-specific alkaline phosphatase, osteocalcin, renal excretion of pyridinolin- and desoxypyridinolin-collagen-crosslinks, serum levels of parathormon, 1,25-dihydroxycholecalciferol and calcium, daily urinary calcium excretion) were investigated in 20 patients with RA. The treatment with 1 alpha-hydroxycholecalciferol resulted in an insignificant decrease in the number of swollen and tender joints, morning stiffness, CRP and ESR. Furthermore, a non-significant decrease in serum levels of TNF-alpha and IL-6 and an increase in IL-4 was observed. The treatment led to a significant decrease of bone-specific alkaline phosphatase (p = 0.001), osteocalcin (p = 0.04) and renal excretion of pyridinolin-crosslinks (p = 0.022) and to an increase of both serum calcium (p = 0.01) and daily urinary calcium excretion (p = 0.004). The results of this pilot study in a small group of RA patients indicate that an adjuvant therapy with active vitamin D metabolites may not only have preventive effects on systemic bone loss but also may inhibit the inflammatory and destructive process in RA in a limited degree.
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PMID:[Vitamin D metabolites in rheumatoid arthritis: findings--hypotheses--consequences]. 1076 32

An immunocytochemical staining method has been developed for simultaneous staining of both cell surface markers (CD4 and CD8) and intracellular cytokine proteins IFN-gamma, IL-4 and IL-5. Cell surface molecules were visualized with alkaline phosphatase, which was developed by Fast Blue BB. Intracellular cytokine proteins were detected by amino-ethyl carbazole. We applied this technique to T cells from T-cell lines and T-cell clones, peripheral blood mononuclear cells and broncho-alveolar lavage fluid cells. Cells were used either unstimulated or stimulated for 4 h with 1 ng/ml PMA and 1 microg/ml ionomycin, which proved to be an optimal stimulus taking cytokine staining, cell recovery and cell viability into account. We studied peripheral blood mononuclear cells from healthy subjects and found that without in vitro stimulation on average 0.4% of the cells were IFN-gamma positive cells. In unstimulated broncho-alveolar lavage fluid cells of the 2 allergic asthmatic subjects studied so far we found higher numbers of cytokine-positive cells (up to 22% of the lymphocytes being IL-4+ cells). By in vitro stimulation, the numbers of cytokine-positive peripheral blood mononuclear cells from the healthy subjects were increased to maximally 5% IFN-gamma+ cells. In stimulated lavage fluid cells from allergic asthmatic subjects maximally 34% of the lymphocytes became IFN-gamma+. We conclude that this method allows detection of intracellular cytokine proteins in both CD4+ and CD8+ T cells without the need for stimulating the cells in vitro. In vitro stimulation may change the cytokine profile detected.
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PMID:Double staining of intracellular cytokine proteins and T-lymphocyte subsets. Evaluation of the method in blood and bronchoalveolar lavage fluid. 1080 80

Interleukin-4 (IL-4) inhibits the spontaneous and stimulated bone resorption resulting from the inhibition of osteoclast formation, as well as osteoclastic activity. Since IL-13 shares some biological properties with IL-4, it was recently reported that IL-13 inhibits bone resorption. The present study was designed to determine the effects of murine IL-4 (IL-4) and murine IL-13 (IL-13) on the murine osteoblastic cell line MC3T3-E1. IL-4 and IL-13 stimulated 3H-thymidine incorporation in the MC3T3-E1 cells and its proliferation in dose dependent manners. A spontaneous increase in alkaline phosphatase (ALP) activity in the cells after plating was inhibited by IL-4 or IL-13, and both cytokines blunted an increase in ALP activity by human parathyroid hormone (PTH) (1-34). PTH-stimulated cyclic AMP (cAMP) production was inhibited by pretreatment with IL-4 and IL-13 for 48 hr in dose dependent manners. Pretreatment with IL-4 and IL-13 for 48 hr caused a decrease in PTH-induced cAMP production at any stimulatory concentration. However, the effective dose (ED50) was unchanged by the pretreatment with these cytokines. Pretreatment with IL-4 and IL-13 did not modulate cAMP generation by forskolin. In contrast, cAMP generation by PGE2 is greater in the cells treated with the cytokines compared to those without the cytokines. These results indicate that IL-4 and IL-13 act on MC3T3-E1 cells in the same manner, stimulating cell proliferation, but inhibiting cell differentiation. The inhibition of osteoblast differentiation by IL-4 and IL-13 may be associated with a decrease in PTH actions on osteoblasts.
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PMID:Interleukin (IL)-4 and IL-13 inhibit the differentiation of murine osteoblastic MC3T3-E1 cells. 1103 73

Pemphigus vulgaris and pemphigus foliaceus are commonly known as antibody-mediated bullous diseases. However, recently a role for infiltrating cells as contributors to the pathogenesis of these diseases has been suggested. The aims of our study were to characterize the immunophenotype of the cellular infiltrate of pemphigus lesional skin and to study the cytokines secreted. We have therefore performed an immunohistochemical study with a large panel of monoclonal antibodies (to CD3, CD4, CD8, CD25, CD30, myeloperoxidase, eosinophil cationic protein EG2, tryptase, human interleukin (IL)-2, human IL-4, human IL-5, human IL-6, human IL-8, and interferon (IFN)-gamma using the alkaline phosphatase-antialkaline phosphatase procedure on lesional and uninvolved skin of six patients with clinical, histological, and immunofluorescent proven pemphigus. We also performed RT-PCR in order to demonstrate mRNA expression of the cytokines of interest. Our results suggest the presence of a T cell population with a prevalent Th2-like cytokine pattern in lesional skin. In addition, we demonstrate a consistent number of granulocytes and mast cells that show clear signs of activation. These data suggest the involvement of an inflammatory infiltrate in the production of pemphigus lesions. In particular, we assume that Th2 cells may be implicated in the very early stages of autoimmune response, concluding that they exert broad activity in blister formation.
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PMID:Further support for a role for Th2-like cytokines in blister formation of pemphigus. 1116 84

Mercuric chloride (HgCl2) is an industrial agent with toxic effects on the immune system, kidney, lung, and nervous tissue, but little is known about its effect on bone. Metallothionein (MT) is a cysteine-rich metal-binding protein that exerts cytoprotective effects against heavy metal toxins. It has been reported that the susceptibility of renal and pulmonary toxicity of mercury was markedly enhanced in MT-null mice compared to control mice. However, there is no report about the effects of anti-metallothionein (anti-MT) Ab induction on mercury toxicity. We investigated the effect of anti-MT Ab induction on mercury-induced bone injury. BALB/c mice were injected with MT (10 microg/mouse ic) five times to induce anti-MT Ab and then treated with HgCl2 (1 mg/kg sc) three times per week for 3 weeks. MT immunization plus HgCl2 treatment dramatically decreased bone mineral density (BMD), and the humoral bone formation indices, alkaline phosphatase (ALP) activity and osteocalcin. MT immunization or HgCl2 treatment alone did not affect either BMD or serum ALP activity and osteocalcin levels. MT immunization impeded HgCl2-induced increase of MT expression in the liver and led to an increase of mercury in serum and the liver but a decrease in the kidney. Furthermore, serum titers of IgE and IgG1 were significantly elevated in the MT-immunized plus HgCl2 treatment group compared with those in the HgCl2 treatment group. Similar results were also observed in splenic secretions of IL-4 and IL-10 based on anti-CD3 Ab stimulation. Taken together, our results indicate that anti-MT Ab induction causes mercury-induced bone injury in BALB/c mice and also enhances mercury-related immune disorders.
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PMID:Induction of anti-metallothionein antibody and mercury treatment decreases bone mineral density in mice. 1249 Jan 34

We determined the extent of expression of three cytokines (IFN-gamma, IL-4, and TNF-alpha ) in brain tissue infected with human immunodeficiency virus-1 (HIV-1). The selections were IFN-gamma as a Th1 cytokine, IL- 4 as a Th2 cytokine, and TNF-alpha as a pro-inflammatory cytokine (and because of its prior implication in brain tissue damage due to HIV-1 infection). Based on current models for pathogenesis of HIV-1-associated dementia (HAD), in the periphery, Th1 cytokines are considered to be salutary, whereas Th2 cytokines are regarded as deleterious. However, we hypothesized that in the CNS these roles are reversed. Post-mortem temporal lobe tissue specimens from 16 HIV-1-seropositive patients and 11 HIV-1-seronegative controls were stained for IFN-gamma, IL-4, and TNF-alpha utilizing immunohistochemistry and alkaline phosphatase. HIV-1 infection causes alterations of brain cytokine expression that include increased IFN-gamma expression for HIV-1-seropositive vs. HIV-1-seronegative individuals. There was increased expression of IFN-gamma for HIV-1-seropositive individuals with or without HAD, with or without the broader category of neuropsychiatric impairment (NPI), and with or without opportunistic infections (OIs) compared to HIV-1-seronegatives. A significant inverse correlation between IFN-gamma vs. IL-4 in HIV-1-seropositives with HAD and in seronegative individuals was observed. There was an inverse correlation in seropositives between IFN-gamma vs. TNF-alpha, a positive trend with HAD, significant without HAD, significant with NPI and significant without OIs. Between IL-4 vs. TNF-alpha there was a correlation (trend) in seropositives, a trend with NPI, significant without NPI, and a trend without OI. Due to HIV-1 infection of the brain and neurological disease there is a prominent increased expression of IFN-gamma, an inverse expression of IFN-gamma vs. TNF-alpha, and TNF-alpha vs. IL-4. The inverse correlation between increased IFN-gamma and decreased IL-4 expression is consistent with the stimulation of activated macrophages, and T cells, greater toxicity in the HIV-1-infected brain, and is supportive of the significance of IFN-gamma in HIV-1-infected patients.
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PMID:Elevated expression of IFN-gamma in the HIV-1 infected brain. 1497 30


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