Protective Effect Of IFN-gamma Research Articles

A little stress is good: IFN-γ, demyelination, and multiple sclerosis

The exact role(s) of the cytokine IFN-gamma in the demyelinating disease multiple sclerosis remain controversial, with evidence suggesting both detrimental and protective effects of the cytokine in MS and MS models such as EAE. The study by Lin and coworkers in this issue of the JCI produces evidence that protective effects of IFN-gamma on mature oligodendrocytes during EAE induction are mediated via activation of the pancreatic ER kinase (PERK), resulting in induction of the endoplasmic reticular stress response pathway (see the related article beginning on page 448). Modulation of this stress pathway has what we believe to be novel therapeutic potential for MS.

Th1-derived cytokine IFN-gamma is a potent inhibitor of eotaxin synthesis in vitro.

Eotaxin potentially plays an integral role in tissue eosinophilia. Inasmuch as Th2-derived cytokine IL-4 has been shown to stimulate eotaxin generation, we investigated here the effect of Th1-derived cytokine IFN-gamma on human eotaxin production. IFN-gamma but not -alpha or -beta potently inhibited tumor necrosis factor (TNF)-alpha-induced eotaxin generation by dermal fibroblasts. The inhibitory effect was unique to eotaxin, because production of IL-8 or monocyte chemoattractant protein (MCP)-1 protein was not affected by the treatment with IFN-gamma. Furthermore, the suppressive effect of IFN-gamma was not cell-type or stimulus specific. The level of eotaxin mRNA increased within 2 h after activation with TNF-alpha and continued to increase up to 72 h. IFN-gamma did not inhibit, but rather augmented the TNF-alpha-induced accumulation of mRNA in the early phase ( approximately 6 h). However, in the later phase, IFN-gamma completely prevented the subsequent elevation of eotaxin mRNA and sustained it at low levels. Although the protective effect of IFN-gamma against allergic inflammation has been assumed to result from its sole regulation of the proliferation of Th2-type T lymphocytes, these results imply that IFN-gamma can also directly act on stromal cells to inhibit eotaxin production and consequently intervene in eosinophil recruitment.

The influence of HLA B27 and interferon-gamma on the invasion and persistence of yersinia in primary human fibroblasts.

To examine the role of the human HLA class I molecule B27 in the direct interaction of yersinia and human cells we performed experimental infections of constitutive HLA B27-positive and -negative human fibroblast monolayers with Yersinia enterocolitica O.3. The numbers of yersiniae invading HLA B27-positive cells were within the range of HLA B27-negative cells. Treatment of fibroblasts with interferon-gamma (IFN-gamma) to enhance HLA B27 expression did not alter invasion. IFN-gamma reduced titers of live intracellular bacteria, but not bacterial antigens, in a dose-dependent manner. Persistent infection with yersinia could be maintained for up to 10 weeks with decreasing bacterial titers and more slowly decreasing amounts of yersinial antigens in HLA B27-positive and -negative cells. Endogenous HLA B27 does not modulate the direct interaction of yersiniae with primary human fibroblasts. This is in contrast to infection of HLA B27-transfected murine cells. The protective effect of IFN-gamma for yersinia-infected cells may be important for controlling complications in patients with yersiniosis.

Susceptibility to Leishmania major in IL-4 transgenic mice is not correlated with the lack of a Th1 immune response.

IL-4 transgenic mice of C3H genetic background expressing IL-4 under the control of an MHC class I promoter were infected with Leishmania major and the immune response was assessed. In contrast to littermate control mice, the transgenic mice were unable to restrict the growth of the parasites as shown by the strong increase in footpad swelling and parasite numbers in the spleen. The observed susceptibility was markedly less severe than that observed in BALB/c mice. Restimulation of lymph node cells with L. major antigen in vitro and subsequent analysis of cytokine secretion revealed that, in contrast to BALB/c mice, the cells from the IL-4 transgenic mice secreted more IL-5 and similar amounts of IFN-gamma as did the cells from litter mate control mice. These results demonstrate that the transgenic expression of IL-4 in vivo leads to the generation of more Th2 cells without affecting the generation of IFN-gamma-producing Th1 cells. This indicates that under certain conditions Th1 and Th2 immune responses during infection with L. major are not mutually exclusive, and that other factors besides the secretion of IL-4 determine whether only a Th1 or a Th2 immune response develops. The observed susceptibility of IL-4 transgenic mice to L major was not due to the lack of IFN-gamma production but presumably to the transgenic and Th2 cell-derived IL-4 counteracting the otherwise protective effect of IFN-gamma on infected macrophages. Our results might help explain why humans develop cutaneous leishmaniasis even though IFN-gamma-producing cells are readily detectable in the lesions.

Protective effects of interferon-gamma in intraocular herpes simplex type 1 infection do not depend on major histocompatibility complex class I or class II expression.

Intraocular infection with herpes simplex virus type I strain F (HSV-1) induces bilateral retinitis, the expression of both MHC class I and II molecules and activation of CD4 and CD8 cells. To investigate the role of MHC upregulation in IFN-gamma mediated antiviral effects in intraocular infection with HSV-1, we infected MHC deficient mice and mice with an additional ectopic site of IFN-gamma production in their retina (rho gamma) intravitreally with HSV-1 into one eye. Protective effects of IFN-gamma in intraocular HSV-1 infection were notable as sparing of the contralateral non-inoculated eye from retinitis, and were not dependent on MHC class I and class II expression, thus limiting the importance of MHC expression for the outcome of viral infection in vivo.

Effects of gamma-interferon on human neutrophils: protection from deterioration on storage

Human polymorphonuclear leukocytes (PMN) preincubated overnight with 100 U/mL gamma-interferon (IFN-gamma) had an increased metabolic response, as measured by iodination and/or superoxide production, to stimulation by tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF), formylmethionyl-leucyl- phenylalanine (FMLP), opsonized zymosan, and lipopolysaccharide (LPS), as compared with cells comparably preincubated in the absence of IFN- gamma. The decline in the staphylocidal activity of the stored PMN was also prevented in part by IFN-gamma, as was the depressed adherence of PMN stimulated with phorbol myristate acetate (PMA), FMLP, TNF, GM-CSF, and LPS. This protective effect of IFN-gamma on PMN function was associated with the prolonged surface expression of the complement receptor three (CR3) alpha-chain (CD11b), CR3 beta-chain (CD18), FcRII (CD32), and FcRIII (CD16), and the appearance of surface FcRI (CD64). The polymerase chain reaction (PCR) was used to amplify neutrophil RNA- derived cDNA recognized by synthetic oliogonucleotides designed from published nucleotide sequences for specific proteins. Using this procedure, mRNA for gp91-phox, p67-phox, p47-phox, CD64, two forms of CD32, CD16, CD11b, CD18, and actin were found to be depressed after overnight storage of neutrophils, and this decrease in steady-state mRNA levels was in part or totally prevented by IFN-gamma. CD64 and gp91-phox mRNA were generally increased by IFN-gamma to a level greater than that of freshly isolated neutrophils. Northern analysis of CD64 and p47 phox mRNAs confirmed the findings with the PCR method. These findings suggest that storage of PMN in a functionally active state is favored by the presence of IFN-gamma.

Effects of γ-Interferon on Human Neutrophils: Protection From Deterioration on Storage

Human polymorphonuclear leukocytes (PMN) preincubated overnight with 100 U/mL gamma-interferon (IFN-gamma) had an increased metabolic response, as measured by iodination and/or superoxide production, to stimulation by tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF), formylmethionyl-leucyl-phenylalanine (FMLP), opsonized zymosan, and lipopolysaccharide (LPS), as compared with cells comparably preincubated in the absence of IFN-gamma. The decline in the staphylocidal activity of the stored PMN was also prevented in part by IFN-gamma, as was the depressed adherence of PMN stimulated with phorbol myristate acetate (PMA), FMLP, TNF, GM-CSF, and LPS. This protective effect of IFN-gamma on PMN function was associated with the prolonged surface expression of the complement receptor three (CR3) alpha-chain (CD11b), CR3 beta-chain (CD18), FcRII (CD32), and FcRIII (CD16), and the appearance of surface FcRI (CD64). The polymerase chain reaction (PCR) was used to amplify neutrophil RNA-derived cDNA recognized by synthetic oliogonucleotides designed from published nucleotide sequences for specific proteins. Using this procedure, mRNA for gp91-phox, p67-phox, p47-phox, CD64, two forms of CD32, CD16, CD11b, CD18, and actin were found to be depressed after overnight storage of neutrophils, and this decrease in steady-state mRNA levels was in part or totally prevented by IFN-gamma. CD64 and gp91-phox mRNA were generally increased by IFN-gamma to a level greater than that of freshly isolated neutrophils. Northern analysis of CD64 and p47 phox mRNAs confirmed the findings with the PCR method. These findings suggest that storage of PMN in a functionally active state is favored by the presence of IFN-gamma.