Bacterial cell wall-induced immunosuppression. Role of transforming growth factor beta.

Wahl, Sharon M.; Hunt, D A; Bansal, Gulshan; McCartney-Francis, Nancy; Ellingsworth, L R; Allen, Julie K.

doi:10.1084/jem.168.4.1403

Cited by 81 publications

(38 citation statements)

References 32 publications

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“…Suppression ofhuman IFN-y biological activity (24) and gene expression (11) has very recently been attributed to a similarly autoinducible lymphokine, TGF/3 . It has been shown that TGF-/3 is an immunosuppressive cytokine produced by rat macrophages (25). We have recently identified TGF0 in a murine MLR supernatant and shown it to be a physiologic downregulator of murine IFN-y gene expression (26).…”

Section: Resultsmentioning

confidence: 99%

Human gamma interferon strongly upregulates its own gene expression in peripheral blood lymphocytes.

Hardy

Sawada

1989

The Journal of Experimental Medicine

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IFN-y occupies a central role as a potent modulator of both the affector and the effector limbs of the immune response . While promising as a therapeutic agent for immunodeficiency states, infectious and neoplastic diseases, and autoimmunity (1-3), IFN-y has perhaps more often been evoked in the pathogenesis of such disorders (4-9). In the latter regard particularly, recent evidence from transgenic mouse models has clearly demonstrated that overexpression of IFN-y can result in autoimmune destruction of tissues by inflammatory mechanisms (10). In the course of studying the cell and molecular basis for IFN-y gene regulation (11), we observed an IFN response consensus sequence in the most proximal 5' region of the human IFN-y gene very near a T cell-specific, inducible DNAse I hypersensitive site 250 by from that gene's cap site (12). Given the role of such response elements in upregulating IFN responsive genes (13, 14), we queried whether the product ofthe human IFN-y gene locus might somehow affect its own expression. In this article, definitive evidence is presented using both total human PBMCs and specific subsets ofthose cells, demonstrating a strong IFN-y autosuperinduction response to either IFN-y "priming or costimulation .Volume 170 September 1989170 September 1021170 September -1026 Materials and Methods Brief Definitive ReportFor each experiment, human PBMC were isolated from 1 U of heparin-treated, random donor buffy coats (GulfCoast Regional Blood Center, Houston, TX) . All samples used were negative by HIV and hepatitis serologies. PBMC were isolated by isoïymph gradient centrifugation . Mixed leukocytes were washed in HBSS and suspended in RPMI 1640, 10% FCS, penicillin/streptomycin at 5 x 106 cells/ml before stimulation. PBMC separated into E+ and E-fractions (15) were first panned in plastic petri dishes at 37°C for 45 min to remove adherent cells . For reconstitution experiments, adherent monocytes from 3 x 107 cells were added back to equal numbers of rosetted cells before stimulation. For co-stimulati experiments, human rIFN-y (Genzyme Corp., Boston, MA) and PHA (final 1.0 g/ml) were added simultaneously, the mixture was incubated at 37°C for 6 h, and nonadherent cells were removed, washed three times in cold PBS, and used directly for total RNA isolation . In preincubation (primed) experiments, cells as above were first incubated with rIFN (or media alone) for 6 h at 37°C before addition of PHA . Preincubation of monocytes alone with IFN-y had no effect on subsequent upregulation of IFN-y transcripts . IFN-y-primed

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Section: Resultsmentioning

confidence: 99%

Human gamma interferon strongly upregulates its own gene expression in peripheral blood lymphocytes.

Hardy

Sawada

1989

The Journal of Experimental Medicine

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“…In addition to modulating FcyRIII expression, TGF-f is a potent inhibitor of immunologic functions in vitro and in vivo (25,(46)(47)(48)(49), and it is possible that enhanced levels ofTGF-,3 in patients with AIDS may also contribute to the immunosuppressed state of these individuals. T and B lymphocytes produce TGF-f3 when stimulated (50,51), as do cells of monocyte lineage (52)(53)(54).…”

Section: Discussionmentioning

confidence: 99%

Association of circulating receptor Fc gamma RIII-positive monocytes in AIDS patients with elevated levels of transforming growth factor-beta.

Allen

Wong²,

Guyre³

et al. 1991

J. Clin. Invest.

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139

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“…Lewis rats were injected on day 0 with SCW and their Al determined daily thereafter. On day 10, half of the animals (filled circles) were begun on a daily dosing regimen of 5 ,ug TGFfl/animal (i.p.). Joint scores for control animals were as indicated in Fig.…”

Section: Methodsmentioning

confidence: 99%

“…TGF,B has been shown in vitro to inhibit proliferation of thymocytes (1), T and B lymphocytes (2)(3)(4)(5), and the less differentiated hematopoietic progenitor cells (6)(7)(8)(9). In addition, it suppresses B cell production of IgG and IgM (2) and antagonizes the immunoregulatory effects ofinterleukins-1, -2, and -3 (2-4, 10), colony stimulating factors (8,10), and interferons alpha ( 11) and gamma (12).…”

Section: Introductionmentioning

confidence: 99%

Transforming growth factor beta 1 suppresses acute and chronic arthritis in experimental animals.

Brandes

Allen²,

Ogawa³

et al. 1991

J. Clin. Invest.

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207

106

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Systemic administration of the cytokine, TGF,f1, profoundly antagonized the development of polyarthritis in susceptible rats. TGF,81 administration (1 or 5 ,g/animal), initiated one day before an arthritogenic dose of streptococcal cell wall (SCW) fragments, virtually eliminated the joint swelling and distortion typically observed during both the acute phase (articular index, AI = 2.5 vs. 11; P < 0.025) and the chronic phase (Al = 0 vs. 12.5) of the disease. Moreover, TGF,61 suppressed the evolution of arthritis even when administration was begun after the acute phase ofthe disease. Histopathological examination of the joint revealed the systemic TGF,81 treatment greatly reduced inflammatory cell infiltration, pannus formation, and joint erosion. Consistent with the inhibition of inflammatory cell recruitment into the synovium, TGF,81 reversed the leukocytosis associated with the chronic phase of the arthritis. Control animals subjected to the same TGF,&1 dosing regimen displayed no discernable immunosuppressive or toxic effects even after 4 wk of treatment. These observations not only provide insight into the immunoregulatory effects of TGF#, but also implicate this cytokine as a potentially important therapeutic agent. (J. Clin.

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Bacterial cell wall-induced immunosuppression. Role of transforming growth factor beta.

Cited by 81 publications

References 32 publications

Human gamma interferon strongly upregulates its own gene expression in peripheral blood lymphocytes.

Human gamma interferon strongly upregulates its own gene expression in peripheral blood lymphocytes.

Association of circulating receptor Fc gamma RIII-positive monocytes in AIDS patients with elevated levels of transforming growth factor-beta.

Transforming growth factor beta 1 suppresses acute and chronic arthritis in experimental animals.

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