Cytokines and Malaria Parasitemia

Jason, Janine; Archibald, Lennox K.; Nwanyanwu, Okey; Bell, Michael; Buchanan, Ian; Larned, Joshua; Kazembe, Peter N.; Dobbie, Hamish; Parekh, Bharat; Byrd, Martha G.; Eick, Angelia A.; Han, Alison; Jarvis, William R.

doi:10.1006/clim.2001.5057

Cited by 61 publications

(51 citation statements)

References 39 publications

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“…51,52 Several studies have provided evidence for a role of hIL-10 in the pathogenesis of B-cell lymphoproliferations and B-cell lymphomas. 53 Human IL-10 was found not only to be produced by BLs, HLs, AIDS-associated lymphomas, and posttransplantation lymphoproliferative diseases (PTLDs) but also to be an autocrine growth factor for some of these malignancies.…”

Section: Discussionmentioning

confidence: 99%

IL-10 can induce the expression of EBV-encoded latent membrane protein-1 (LMP-1) in the absence of EBNA-2 in B lymphocytes and in Burkitt lymphoma- and NK lymphoma-derived cell lines

Kis

Takahara

Nagy

et al. 2006

Blood

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IntroductionThe human gammaherpesvirus Epstein-Barr virus (EBV) is ubiquitous and it persists for the lifetime of the individual after the first encounter. In spite of the efficient transforming potential of the virus for B lymphocytes in vitro, the infection with EBV is largely harmless in vivo due to the vigorous immune response directed against the virus-encoded proteins expressed in proliferating cells, 1 combined with the viral strategy to downregulate the expression of the immunogenic viral proteins in the infected memory B cells. 2 A variety of lymphomas and carcinomas were found to carry EBV genome and to express virally encoded proteins. 1 Except for the lymphomas in immunosuppressed individuals, the role of the virus in the genesis of the tumors is unknown.EBV readily infects B-lymphocyte cultures in vitro and transforms them into proliferating lymphoblastoid cell lines (LCLs). These cells carry the virus in a latent form and express a set of viral genes that in concert with cellular genes induce the immunoblastic transformation and proliferation of the B cells. 1 The emerging lymphoblastoid cell lines (LCLs) express 6 nuclear (EBNA1-6) and 3 membrane viral proteins (latent membrane protein 1 [LMP-1], -2A, -2B). This expression pattern is termed type III latency or growth program. 1,2 In this program the expression of LMPs is driven by the trans-activator EBNA-2 together with EBNA-5 (EBNA-2-dependent expression of LMPs). 1 In EBV-positive malignant cells the virus expresses only a few viral genes, such as only EBNA-1 in Burkitt lymphoma (BL), whereas in nasopharyngeal carcinoma, 3 Hodgkin lymphoma, 4 and T and NK lymphomas 5 EBNA-1 is expressed together with LMP-1 and LMP-2 (EBNA-2-independent LMP expression). 1 EBER and BART RNAs are expressed in all latency forms. 1 LMP-1 is required for in vitro transformation and proliferation of B cells in vitro. 6,7 Acting as a constitutively active receptor, 8 LMP-1 activates similar pathways as the triggering of the CD40 receptor and is therefore regarded as a functional homologue of CD40.B cells with all 3 EBV latency types have been detected in the lymphoid tissues of patients with clinically manifest primary EBV infection (infectious mononucleosis [IM]) and also in healthy EBV carriers. 2 In healthy individuals, transcripts of type III latency-associated genes were found exclusively in naive B cells, whereas germinal center (GC) and memory B cells expressed the restricted type II and type I latency, respectively. 2 It has been proposed that EBV exploits the normal B-cell differentiation pathway to get access to the memory compartment. LMP-1 and LMP-2A are believed to provide survival signals for the EBV-infected GC B lymphocytes by mimicking the externally activated CD40 and B-cell receptor (BCR) pathways, respectively.Type II latent B cells were also found by immunohistochemical analysis of tonsillar sections of healthy EBV carriers 9 and IM patients. 10 Furthermore, rare B cells expressing type II EBV latency were detected in several lymphoid malignancies,...

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Section: Discussionmentioning

confidence: 99%

IL-10 can induce the expression of EBV-encoded latent membrane protein-1 (LMP-1) in the absence of EBNA-2 in B lymphocytes and in Burkitt lymphoma- and NK lymphoma-derived cell lines

Kis

Takahara

Nagy

et al. 2006

Blood

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“…During three periods in 1997 and 1998, we enrolled all 561 febrile (oral temperature, Ն38°C) adults (Ն13 years old) and all 244 acutely ill children (Ͻ13 years old) admitted to Lilongwe Central Hospital, Malawi, Africa, into a study of bloodstream infections (10,11). All hospitalized children were included because infected children often do not present with fever.…”

Section: Methodsmentioning

confidence: 99%

“…by enzyme-linked immunosorbent assays using pairs of cytokine-specific monoclonal antibodies according to the manufacturers' instructions. Details are provided elsewhere (11). No healthy participants and few children had serum cytokines assessed (see Results).…”

Section: Methodsmentioning

confidence: 99%

“…We ourselves have rarely, if ever, noted spontaneous cytokine production in PBMCs of healthy U.S. blood donors (reference 7 and unpublished data). However, in a multicenter, multiphase study of the immune correlates of bloodstream infections in developing countries (8,10,11), we noticed individuals whose PBMCs produced cytokines without stimulation. Other researchers, measuring either protein or mRNA, have detected spontaneous cytokine production by bronchoalveolar lavage fluid cells of patients with asthma (4), interacting umbilical vein endothelial cells-monocyte cells (17), human milk mononuclear cells (20), peripheral blood lymphocytes of persons with atopic dermatitis (19,23), peripheral blood monocytes of patients with multiple sclerosis (3), or CD4 ϩ T cells of persons with active Mycobacterium tuberculosis pulmonary infection (2).…”

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confidence: 97%

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Spontaneous Cytokine Production and Its Effect on Induced Production

Walker

Jason

Wallace

et al. 2002

Clin Vaccine Immunol

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Cytokines regulate cellular immune activity and are produced by a variety of cells, especially lymphocytes, monocytes, and macrophages. Multiparameter flow cytometry is often used to examine cell-specific cytokine production after in vitro phorbol 12-myristate 13-acetate and ionomycin induction, with brefeldin A or other agents added to inhibit protein secretion. Spontaneous ex vivo production reportedly rarely occurs. We examined the spontaneous production of interleukin 2 (IL-2), IL-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-␣), and gamma interferon (IFN-␥) by peripheral-blood B lymphocytes, T cells, CD8 We also evaluated the relationship between spontaneous and induced cytokine production. In patients, spontaneous TNF-␣ production occurred most frequently, followed in descending order by IFN-␥, IL-8, IL-4, IL-10, IL-6, and IL-2. Various cells of 60 patients spontaneously produced TNF-␣; for 12 of these patients, TNF-␣ was the only cytokine produced spontaneously. Spontaneous cytokine production was most frequent in the immunoregulatory cells, NK and NT. For IL-2, IL-4, IL-6, IL-8, and IL-10, spontaneous cytokine production was associated with greater induced production. For TNF-␣ and IFN-␥, the relationships varied by cell type. For healthy adults, IL-6 was the cytokine most often produced spontaneously. Spontaneous cytokine production was not unusual in these acutely ill and healthy persons living in an area where human immunodeficiency virus, mycobacterial, malaria, and assorted parasitic infections are endemic. In such populations, spontaneous, as well as induced, cell-specific cytokine production should be measured and evaluated in relation to various disease states.

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“…Presumably included among these host responses are those that are controlled by the pleiotropic cytokine IL-6, with its pro-and anti-inflammatory activities (4). Circulating IL-6 levels are increased in patients suffering from malaria caused by P. falciparum and P. vivax (5)(6)(7)(8), which is often associated with polyclonal B cell activation (9). Conversely, decreasing IL-6 levels were described after antimalarial treatment (10) and are associated with decreasing hyperpyrexia (11) and decreasing parasitemia (12).…”

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confidence: 99%

Cutting Edge: Inhibition of IL-6 Trans-Signaling Protects from Malaria-Induced Lethality in Mice

Wunderlich

Delić

Behnke

et al. 2012

The Journal of Immunology

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Circulating IL-6 levels correlate with the severity of blood-stage malaria in humans and mouse models, but the impact of IL-6 classic signaling through membrane IL-6Rα, as well as IL-6 trans-signaling through soluble IL-6Rα, on the outcome of malaria has remained unknown. In this study, we created IL-6Rα–deficient mice that exhibit a 50% survival of otherwise lethal blood-stage malaria of the genus Plasmodium chabaudi. Inducing IL-6 trans-signaling by injection of mouse recombinant soluble IL-6Rα in IL-6Rα–deficient mice restores the lethal outcome to malaria infection. In contrast, inhibition of IL-6 trans-signaling via injection of recombinant sGP130Fc protein in control mice results in a 40% survival rate. Our data demonstrate that IL-6 trans-signaling, rather than classic IL-6 signaling, contributes to malaria-induced lethality in mice, preceded by an increased inflammatory response. Therefore, inhibition of IL-6 trans-signaling may serve as a novel promising therapeutic basis to combat malaria.

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Cytokines and Malaria Parasitemia

Cited by 61 publications

References 39 publications

IL-10 can induce the expression of EBV-encoded latent membrane protein-1 (LMP-1) in the absence of EBNA-2 in B lymphocytes and in Burkitt lymphoma- and NK lymphoma-derived cell lines

IL-10 can induce the expression of EBV-encoded latent membrane protein-1 (LMP-1) in the absence of EBNA-2 in B lymphocytes and in Burkitt lymphoma- and NK lymphoma-derived cell lines

Spontaneous Cytokine Production and Its Effect on Induced Production

Cutting Edge: Inhibition of IL-6 Trans-Signaling Protects from Malaria-Induced Lethality in Mice

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