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Biomedical subjects

K A Rockett

Publications and source records attributed to K A Rockett.

At least 19 recordsLinked to original sources
PubMed1998

Variable major lipoprotein is a principal TNF-inducing factor of louse-borne relapsing fever.

Massive release of tumor necrosis factor is responsible for the potentially fatal larisch-Herxheimer reaction that follows antibiotic treatment of relapsing fever due to Borrelia recurrentis. We have undertaken the quantitative purification of the components of B. recurrentis that stimulate human monocytes to produce tumor necrosis factor. We show that the predominant factor inducing tumor necrosis factor is a variable lipoprotein homologous to the variable major protein of B. hermsii. We found antibodies to different forms of variable major protein in two patients with louse-borne relapsing fever. The three purified variable major proteins studied here differ in their ability to induce tumor necrosis factor production, which may partly explain the variable clinical severity of borrelial infection. These results may be of considerable relevance for the pathogenesis of Lyme disease and other forms of human borreliosis.

Amino Acid Sequence↗
PubMed1998

1,25-Dihydroxyvitamin D3 induces nitric oxide synthase and suppresses growth of Mycobacterium tuberculosis in a human macrophage-like cell line.

Inducible synthesis of nitric oxide (NO) by macrophages is an important mechanism of the host defense against intracellular infection in mice, but the evidence for significant levels of inducible NO production by human macrophages is controversial. Here we report that the human promyelocytic cell line HL-60, when differentiated to a macrophage-like phenotype, acquires the ability to produce substantial amounts of NO on stimulation with LPS or 1, 25-dihydroxyvitamin D3 (1,25-D3) in the absence of activating factors such as gamma interferon. Expression of the inducible nitric oxide synthase (NOS2) was confirmed by sequencing of the reverse transcription-PCR product from stimulated HL-60 cells. Kinetic studies after lipopolysaccharide stimulation show that NOS2 mRNA levels rise within 3 to 6 h, that conversion of [14C]arginine to [14C]citrulline is maximal at 5 to 6 days, and that levels of reactive nitrogen intermediates stabilize at around 20 microM at 7 to 8 days. We find that 1,25-D3 acts to suppress the growth of Mycobacterium tuberculosis in these cells and that this effect is inhibited by NG-monomethyl-L-arginine, suggesting that vitamin D-induced NO production may play a role in the host defense against human tuberculosis.

Calcitriol↗
PubMed1996

Does malarial tolerance, through nitric oxide, explain the low incidence of autoimmune disease in tropical Africa?

Autoimmune disease is generally rare in tropical rural populations. Plasma concentrations of nitrite plus nitrate (reactive nitrogen intermediates), reflecting high nitric-oxide production somewhere in the body, can be high in patients who have cerebral malaria, but even higher in symptom-free parasitised individuals, who are termed malaria-tolerant. We propose that the nitric oxide causing high serum levels of reactive nitrogen intermediates in malaria-tolerant individuals is generated in macrophages during the establishment and maintenance of malarial tolerance, and makes autoimmune disease rare in many tropical rural populations by minimising proliferation of autoreactive T cells. Conversely, innately low levels of nitric-oxide generation in these populations, selected by malarial disease in tropical areas, could rationalise their high frequency of autoimmune disease and hypertension when living in western societies.

Africa↗
PubMed1996

Nitric oxide production is increased during murine vaccinia virus infection, but may not be essential for virus clearance.

Recent reports have highlighted a potential antiviral activity for nitric oxide (NO). The purpose of this study was to investigate the production of NO in mice during vaccinia virus (VV) or herpes simplex virus type 1 infection, and to assess the role of NO in clearance of VV. Reactive nitrogen intermediates (RNI; NO and its stable oxidation products, nitrite and nitrate) were significantly elevated in the plasma of mice infected with these viruses. Furthermore, spleen cells from virus-infected mice produced elevated RNI levels following stimulation in vitro with LPS. NO production during VV infection was critically dependent on the cytokines tumor necrosis factor and interferon-gamma, and on the presence of both CD4+ and CD8+ T lymphocytes. Treatment of VV-infected mice with the nitric oxide synthase inhibitor N(G)-methyl-L-arginine did not alter the course of infection, suggesting that NO may not be essential for the clearance of this virus.

Animals↗
PubMed1996

In vitro induction of nitric oxide by an extract of Plasmodium falciparum.

Malarial illness and pathology is generally accepted to be caused by material released when the infected red cells burst at schizogony. The released material has been partially purified and shown to stimulate macrophages to make TNF. We have extended this work to show that these same preparations, isolated from parasitized erythrocytes, induce the mouse macrophage cell line RAW 264.7 to produce inducible nitric oxide synthase and release nitric oxide. By using cytokine-specific antisera we have found that this induction is independent of TNF and IL-1 alpha and partly independent of IL-1 beta.

Animals↗
PubMed1994

Interleukin-6 and tumor necrosis factor in the pathogenesis of adverse reactions after treatment of lymphatic filariasis and onchocerciasis.

Adverse reactions following treatment of onchocerciasis and bancroftian filariasis are common and frequently severe. They are generally caused not by direct drug toxicity but by host inflammatory responses to dying microfilariae. To define the responsible mechanism, serial blood levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF) were studied in 15 microfilaria-positive patients (10 with bancroftian filariasis, 5 with onchocerciasis) and 4 microfilaria-negative persons after diethylcarbamazine treatment. Elevations in IL-6 correlated with the occurrence and severity of clinical symptoms after treatment; for the onchocerciasis patients IL-6 levels directly reflected pretreatment intensity of infection. Serum TNF levels also rose but did not correlate directly with infection intensity or reaction severity. Microfilaria-negative controls remained asymptomatic with no significant rise in either cytokine. These findings suggest an etiologic role for systemically elevated cytokines in the inflammatory reactions developing after treatment of filarial infections in humans.

Adult↗
PubMed1994

Possible role of nitric oxide in malarial immunosuppression.

We have tested the hypothesis that nitric oxide may be responsible for the immunosuppression reported during malaria infections. We first showed that reactive nitrogen intermediates, which indicate nitric oxide generation, were increased in the plasma of Plasmodium vinckei-infected mice. We next found that Concanavalin A-induced proliferation of spleen cells from these mice was reduced compared with that observed in uninfected animals. The addition of NG-methyl-L-arginine (L-NMMA) for the duration of the cultures restored the malarial proliferative response to normal. We then tested the effect of oral L-NMMA on the proliferative response of P. chabaudi-infected mice to a human red blood cell lysate. The secondary response to this antigen, measured as spleen cell proliferation in vitro ten days after immunization and when there was no discernible parasitaemia, remained normal in L-NMMA-treated P. chabaudi mice, but was decreased in the untreated infected mice. These results suggest a role for nitric oxide in malarial immunosuppression.

Animals↗
PubMed1994

Tumor necrosis factor and interleukin-1 synergy in the context of malaria pathology.

Reports linking human malarial illness and pathology with serum tumor necrosis factor (TNF) levels are now common, although the association is not always precise. Possible reasons for this discrepancy include the reported variation in levels of interleukin-1 (IL-1), a cytokine known to synergize with TNF. We have examined the extent of synergy between recombinant human TNF and either recombinant human IL-1 alpha or recombinant human IL-1 beta in producing hypoglycemia and increasing plasma levels of nitric oxide in malaria (Plasmodium vinckei)-infected CBA mice. Very low concentrations of either IL-1 alpha or IL-1 beta, with negligible effects on their own, greatly enhanced the effectiveness of TNF in bringing about these changes. In particular, synergy in generating nitric oxide, a mediator argued to induce cerebral malaria, was profound. Thus, variation in generation of IL-1 during infection provides one explanation for the poor correlation sometimes encountered between serum TNF levels and clinical condition.

Analysis of Variance↗