Search PubMed⌕ Search

Biomedical subjects

L D Kerr

Publications and source records attributed to L D Kerr.

At least 37 records · Page 2Linked to original sources
PubMed1997

TGF-beta inhibits IL-2-induced tyrosine phosphorylation and activation of Jak-1 and Stat 5 in T lymphocytes.

Signaling through IL-2R, IL-2 induces tyrosine phosphorylation and activation of Jak-1 and Jak-3 kinases and Stat 3 and Stat 5 transcription factors leading to cell cycle progression of activated T cells from G1 to S phase. TGF-beta is an immunosuppressive cytokine, which inhibits T cell proliferation at G1 to S phase transition. We examined the effect of TGF-beta on IL-2R signal transduction pathway in activated T cells. We show here that treatment of activated T cells with TGF-beta inhibited IL-2-induced tyrosine phosphorylation and activation of Jak-1 and Stat 5 but not Jak-3 and Stat 3. TGF-beta also inhibited IL-2-induced expression of alpha- and beta-chains of IL-2R and induced apoptotic cell death in T cells. These results suggest that TGF-beta-induced growth arrest and apoptosis are associated with the modulation of IL-2-induced activation of Jak-Stat pathway in T cells.

Animals↗
PubMed1997

Expression of glutathione and gamma-glutamylcysteine synthetase mRNA is Jun dependent.

The gene GLCLC encodes the catalytic subunit of gamma-glutamylcysteine synthetase (glutamate-cysteine ligase E.C. 6.3.2.2), the rate limiting enzyme for glutathione synthesis. When HepG2 cells were exposed to the serine/threonine phosphatase inhibitor okadaic acid (OA), increased expression of GLCLC was observed, as was the development of resistance to xenobiotic induced GSH depletion. Okadaic acid is known to activate both NF-kappaB and AP-1 activity. Inhibition of NF-kappaB activity by overexpression of an IkappaB alpha transdominant inhibitor or exposure to the protease inhibitor TLCK did not inhibit the OA mediated increase in GLCLC transcripts. Fibroblasts derived from a mouse containing a c-Jun null mutation exhibited diminished AP-1 binding activity, reduced levels of GLCLC message, and a correspondingly low GSH concentration compared to wild type cells. When the null cells, which express Jun B and Jun D, were exposed to OA, AP-1 binding activity increased, as did expression of GLCLC message. These results indicate that AP-1 transcription factors participate in the regulation of glutathione metabolism.

Animals↗
PubMed1996

Protein kinase C isotypes required for phorbol-ester induction of stromelysin-1 in rat fibroblasts.

The phorbol-ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) is a potent inducer of the metalloproteinase stromelysin in fibroblasts in vivo and in several cultured cell lines. Rat-1 and Rat-2 fibroblasts, however, do not respond to TPA stimulation by induction of stromelysin gene activity, although collagenase promoter-mediated activity is induced threefold by TPA treatment in these cells. We determined that rat fibroblasts expressed protein kinase C(PKC)alpha, PKCdelta, PKCepsilon, and PKCzeta but neither the mRNA nor the protein for PKCbeta. When Rat-2 fibroblasts were stably transfected with an expression vector producing PKCbeta, however, TPA treatment of these variants resulted in a 3.1-fold induction of stromelysin promoter-mediated luciferase activity compared with a 1.3-fold induction in parental Rat-2 cells (P<0.002). Transient transfection of PKCepsilon produced a small but significant increase in TPA-stimulation of both stromelysin- and collagenase-mediated gene expression. These results suggest that there are PKC isotype-specific signaling pathways that can differentially regulate matrix metalloproteinase gene expression.

Animals↗
PubMed1995

A reexamination of the relationship between active rheumatoid arthritis and the acquired immunodeficiency syndrome.

Three patients with rheumatoid arthritis (RA) that remitted with the development of the human immunodeficiency virus (HIV) infection have been described in the literature, and this has contributed to the belief that RA and HIV infection or the acquired immunodeficiency syndrome (AIDS) cannot coexist. However, a computerized MEDLINE literature search revealed reports of 4 patients who did have active RA and AIDS or HIV infection, as well as other case reports of symmetric polyarthritis compatible with RA in patients with HIV infection. Each of the patients whose RA remitted had received standard disease-modifying antirheumatic drug therapy, and 1 of the 3 had a normal T helper:T suppressor ratio at the time of remission. Of the 4 previously reported patients with active RA and AIDS or HIV infection, all had decreased numbers of T helper lymphocytes. The present report describes a fifth patient with both RA and AIDS and reviews the data concerning the coexistence of these 2 diseases. It appears that active RA may indeed coexist with AIDS. It remains to be seen under what settings HIV may have a disease-modifying effect in RA. These issues have important implications regarding the pathogenesis and therapy of RA, especially in terms of the role of CD4+ lymphocytes and anti-CD4 monoclonal antibody therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1995

The impact of rheumatology in the primary care setting: one rheumatologist's odyssey.

I report my experience during one 6-month period as the sole rheumatologist running a weekly clinic at a small community hospital. The report illustrates the impact of rheumatologic expertise in an environment well-served by generalists and other medical subspecialists. This experience identifies important gaps in the education of generalists in internal medicine residency training programs. In particular, the ability to recognize and distinguish patients with the two most prevalent rheumatic disorders, rheumatoid arthritis and osteoarthritis, must be taught to generalists more effectively by rheumatologists.

Clinical Competence↗
PubMed1994

Arrested development: understanding v-abl.

The protein tyrosine kinase activity of the v-abl oncogene has been demonstrated to subvert the normal second messenger systems used by lymphoid cells for growth and differentiation. Transformation of bone marrow with the Abelson murine leukemia virus results in the appearance of B cell lineage cells arrested at the pre-B cell stage. Recent reports have characterized these cells expressing high v-abl kinase activity as deficient in detectable NF-kappaB DNA binding activity and low level RAG gene expression. These observations suggest that v-abl may be inhibiting the differentiation of B cells by blocking these two crucial elements in the maturation pathway.

Abelson murine leukemia virus↗
PubMed1994

Correlation of liver and skin histopathology with serology in a patient with cutaneous vasculitis and hepatitis C infection.

A strong body of evidence supports a viral etiology for many forms of vasculitis. Recent literature supports the association of the hepatitis C virus (HCV) with essential mixed cryoglobulinemia. We describe a case of cutaneous vasculitis associated with simultaneous active hepatic inflammation demonstrated by skin and liver biopsies. Immunofluorescence, hepatitis C serology, and study of the cryoprecipitate all confirmed HCV infection and deposition of immune complexes. Treatment with interferon alpha-2b was extremely effective as compared with prednisone and colchicine. This case provides further evidence that active hepatic infection with HCV may be a cause of cryoglobulinemia and cutaneous vasculitis. It also suggests that further studies of antiviral therapy for vasculitis should be explored.

Female↗
PubMed1994

ACTH revisited: effective treatment for acute crystal induced synovitis in patients with multiple medical problems.

OBJECTIVE: To determine the effectiveness of adrenocorticotropic hormone (ACTH) for acute gouty arthritis and pseudogout in a population of patients with multiple coexisting medical problems. METHODS: We retrospectively reviewed our experience with parenteral ACTH 40 or 80 units intravenous, intramuscular, or subcutaneous tid with tapering in the treatment of 38 patients. Thirty-three patients had documented acute gout and 5 patients had documented acute pseudogout. A total of 43 episodes of acute crystal induced synovitis were treated. The indications for using ACTH included congestive heart failure, chronic renal insufficiency, gastrointestinal bleeding, or no response to NSAID: RESULTS: All episodes of pseudogout resolved in an average of 4.2 days. Of the episodes of acute gout, 97% resolved in an average of 5.5 days. Although mild hypokalemia, hyperglycemia, fluid retention and rebound arthritis occurred as adverse effects, none was severe and all were easily controlled. CONCLUSION: ACTH is a safe and effective treatment for acute gout and pseudogout, especially in patients with multiple medical problems.

Adrenocorticotropic Hormone↗
PubMed1993

Association between proto-oncoprotein Rel and TATA-binding protein mediates transcriptional activation by NF-kappa B.

The c-Rel protein is able to associate in vitro and in vivo with the TATA-binding protein (TBP) of the TFIID complex. Coexpression of TBP with c-Rel augments transactivation from the kappa B site in Drosophila Schneider cells. DNA-binding mutants of TBP not only fail to cooperate, but they repress transactivation by c-Rel. There may be a direct communication between kappa B enhancer binding proteins and basal transcription factors which leads to enhanced transcription.

Animals↗
PubMed1993

Myocarditis as a complication in scleroderma patients with myositis.

This report describes six diffuse scleroderma (PSS) patients with skeletal muscle myositis accompanied by severe myocarditis, diagnosed by CPK-MB elevation in conjunction with severe left ventricular (LV) hypokinesis. Although the myositis improved with steroid therapy in all patients, those treated with steroids alone died due to progressive LV failure. This experience suggests that the LV dysfunction in PSS patients with myositis may have an inflammatory component. Since the myocarditis may not be clinically apparent initially, it is suggested that CPK-MB fractionation and studies of LV function are undertaken in all PSS patients with myositis. The optimal treatment of this disorder, however, has yet to be determined.

Adult↗
PubMed1993

Autoantibodies to the protein core of vascular basement membrane heparan sulfate proteoglycan in systemic lupus erythematosus.

Vascular heparan sulfate proteoglycan (vHSPG) has an important role in the normal vasculature, including hemostasis, lipolysis and other vascular functions. These functions are mediated by both the glycosaminoglycan and protein core moieties of vHSPG. Autoimmunity to vHSPG has been demonstrated to play a role in vascular injury in animal models, and is present in patients with autoimmune vascular disease. However, most previous studies of human autoimmunity to vHSPG have only investigated heparan sulfate glycosaminoglycan epitopes. In the current investigations, autoantibodies to the protein core of vHSPG in sera from patients with systemic lupus erythematosus (SLE) were investigated. vHSPG protein core was prepared by chemical deglycosylation. Competitive immunoinhibition ELISA and immunoblotting immunoassays were established employing monoclonal antibodies to vHSPG protein core. SLE sera were demonstrated to contain IgG autoantibodies reactive with the vHSPG protein core by immunoblotting. Human autoantibodies to vHSPG protein core were not inhibited by heparan sulfate confirming their protein core reactivity. Competitive immunoinhibition studies employing a solid phase radioimmunoassay also confirmed the reactivity of human sera with vHPSG protein core. By ELISA, a significant increase in the occurrence of anti-vHSPG protein core antibodies was noted in SLE sera. While most previous investigations have demonstrated autoimmunity to heparan sulfate, the presence of IgG autoantibodies to vHSPG protein core demonstrates that the entire vHSPG proteoglycan is the target of autoimmunity in SLE.

Animals↗
PubMed1993

The bZIP domains of Fos and Jun mediate a physical association with the TATA box-binding protein.

Fos and Jun oncoproteins form a complex that regulates transcription from promoters containing AP-1 binding sites. These two proteins, like other transcriptional activators, are likely to stimulate transcription through direct and/or indirect interactions with members of the basal transcriptional machinery. The ability of c-Fos and c-Jun proteins to interact directly with the TATA box-binding protein (TBP), the general transcription factor required for initiating the assembly of transcription complexes, was investigated. Using co-immunoprecipitation and protein-protein association assays, we show that both c-Fos and c-Jun bind specifically and stably to TBP. Mutational analysis demonstrates that both the basic region and leucine zipper domains of c-Fos and c-Jun are necessary and sufficient for stable association with TBP. A 51-residue region from the conserved C-terminal region of TBP, previously shown to be the binding site for the viral activator protein E1A, interacts with c-Fos and c-Jun proteins. We propose that c-Fos and c-Jun proteins function as transcriptional activators, in part by recruiting TBP to form complexes to initiate RNA synthesis.

Amino Acid Sequence↗
PubMed1993

Scleroderma following silicone implantation: a cumulative experience of 11 cases.

In the 3 years since the initial report of 5 patients who developed scleroderma in association with silicone breast implants, 6 additional silicone implant recipients have presented with scleroderma. Two of these patients received silicone chin implants. A total of 5 patients elected to remove their prostheses. Two patients have had marked improvement of cutaneous scleroderma. The other 3 patients, however, died secondary to progressive visceral involvement. This cumulative experience of 11 cases of scleroderma following silicone implantation suggests additional evidence of an association between the 2. Careful case control studies over an extended period of time are required to determine the incidence of this outcome.

Adult↗
PubMed1992

Direct association of pp40/I kappa B beta with rel/NF-kappa B transcription factors: role of ankyrin repeats in the inhibition of DNA binding activity.

To understand the mechanism by which pp40/I kappa B beta inhibits DNA binding activity of the rel/NF-kappa B family of transcription factors, we have investigated the role of ankyrin repeats on the biological function of pp40 by deleting or mutating conserved residues. We show that (i) ankyrin repeats alone are not sufficient to manifest biological activity but require the C-terminal region of the pp40 protein; (ii) four out of the five ankyrin repeats are essential for inhibiting the DNA binding activity; (iii) pp40 mutants that do not inhibit DNA binding of rel protein also do not associate with rel; (iv) although pp40 can associate with the p65 and p50 subunits of NF-kappa B, pp40 inhibits the DNA binding activity of only the p50-p65 heterodimer and the p65 homodimer; and (v) pp40 inhibits the transcription of genes linked to kappa B site; however, mutants that do not affect DNA binding have no effect. We propose that the ankyrin repeats and the C-terminal region of pp40 form a structure that associates with the rel homology domain to inhibit DNA binding activity.

Amino Acid Sequence↗
PubMed1992

I kappa B gamma, a 70 kd protein identical to the C-terminal half of p110 NF-kappa B: a new member of the I kappa B family.

A cDNA corresponding to the 2.6 kb NF-kappa B mRNA species present in a variety of lymphoid cell lines has been molecularly cloned. The deduced 607 amino acid sequence is identical to the sequence of the C-terminal region of 110 kd NF-kappa B protein. A 70 kd protein can be identified in lymphoid cells using antibodies raised against the C-terminal region of p110 NF-kappa B. Comparison of the two-dimensional tryptic peptide maps of the 70 kd protein expressed in cells and the in vitro translated product encoded by the cDNA display extensive homology. The 70 kd protein expressed in bacteria prevents sequence-specific DNA binding of p50-p65 NF-kappa B heterodimer, p50 homodimer, and c-rel. p70 also interferes with transactivation by c-rel and prevents its nuclear translocation. The 70 kd protein, predominantly found in lymphoid cells, is a new member of the I kappa B family of proteins and is referred to as I kappa B gamma.

Amino Acid Sequence↗
PubMed1992

Purified I kappa B-beta is inactivated upon dephosphorylation.

In uninduced cells, the NF-kappa B transcription factor resides in the cytoplasm in complex with an inhibitory protein, I kappa B. I kappa B is a specific inhibitor of DNA binding and apparently prevents nuclear uptake of NF-kappa B. Stimulation of cells, for instance with the cytokine tumor necrosis factor, releases I kappa B and allows nuclear translocation and DNA binding of NF-kappa B to regulatory DNA sequences in many genes. We recently reported on the purification of a major form of I kappa B, referred to as I kappa B-alpha, with a molecular size of 37 kDa. Here, we purified and characterized I kappa B-beta, a chromatographically distinct second form of I kappa B. I kappa B-beta has a size of 43 kDa and, as I kappa B-alpha, an acidic isoelectric point between 4.8 and 5.0. Both forms of I kappa B were inactivated by a treatment with protein kinases A and C in vitro. In contrast to I kappa B-alpha, I kappa B-beta lost its inhibiting activity upon a treatment with phosphatase. Phosphatase treatment also released active NF-kappa B from its inactive complex with I kappa B-beta suggesting that the activation of NF-kappa B in intact cells might not only rely on phosphate transfer onto I kappa B but also on phosphate removal from one form of I kappa B.

Chromatography, Liquid↗
PubMed1992

Negative regulation of gene expression by TGF-beta.

Stromelysin gene expression is transcriptionally activated by a number of growth factors (e.g., EGF and PDGF), tumor promoters (e.g., TPA), and oncogenes (e.g., ras, src) through an AP-1-dependent mechanism. TGF-beta repression of stromelysin induction is mediated at the level of transcription by an element located at position -709 in the rat stromelysin promoter referred to as the TGF-beta inhibitory element (TIE). A TIE-binding protein complex is induced by treatment of rat fibroblasts with TGF-beta. This protein complex contains the protooncogene c-fos, and induction of c-fos by TGF-beta is required for the repressive effects of TGF-beta on stromelysin gene expression. Interestingly, c-fos induction is also required for stimulation of stromelysin expression by EGF in rat fibroblasts. Preliminary studies suggest that differential regulation of members of the jun family of early-response genes may explain this apparent paradox and determine whether stromelysin is induced or repressed by growth factors. TGF-beta stimulation therefore initiates a cascade of events that results in a specific pattern of gene expression: the direct stimulation of early-response genes can lead to subsequent induction or repression of other genes. Growth factor regulation of matrix metalloproteinases appears to play a role in embryonic development in the morphogenesis of the murine lung. Treatment of embryonic lungs in organ culture with the growth factors EGF or TGF-alpha results in stimulation of growth and inhibition of branching morphogenesis. A similar inhibition of branching was observed when these lung rudiments were treated with the matrix metalloproteinase collagenase. Most interestingly, the effects of EGF and TGF-alpha can be completely reversed by the tissue inhibitor of metalloproteinases, TIMP. TGF-beta has the opposite effect on growth of murine lung rudiments--growth is inhibited in a dose-dependent manner. This example illustrates a potential role for growth factor regulation of matrix-degrading metalloproteinases in complex developmental processes.

Animals↗