Major Differences in the Responses of Primary Human Leukocyte Subsets to IFN-β

Boxel-Dezaire, Anette H Van; Zula, Joana A.; Xu, Yaomin; Ransohoff, Richard M.; Jacobberger, James W.; Stark, George Stark

doi:10.4049/jimmunol.0902314

Cited by 65 publications

(67 citation statements)

References 58 publications

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“…Similarly, our previous study of healthy subjects showed significantly fewer CD4 + T cells than monocytes with activated STAT3 in response to 500 IU/mL IFN-β1a in vitro (9). However, we also observed previously, in healthy subjects, by using the same in vitro conditions, that significantly fewer CD4 + T cells and B cells activated STAT1 in comparison with monocytes (9).…”

Section: Resultssupporting

confidence: 86%

“…We previously found significant differences in the activation of STATs 1, 3, and 5 among leukocyte subsets after stimulation of whole blood of healthy donors in vitro with IFNβ1a, and linked these differences to differential induction of apoptosis (9). In a control experiment (Fig.…”

Section: Resultsmentioning

confidence: 80%

“…We hypothesized that differential activation of these various signaling proteins could help to explain cell type-specific induction of apoptosis in response to IFN-α/β (9). In our previous study, by using freshly drawn whole blood from healthy subjects, we observed significant differences in the IFN-β-induced activation of STATs 1, 3, and 5 in primary human T cells, B cells, and monocytes in vitro, with STAT1-dependent gene induction linked to apoptosis in monocytes and STAT3-dependent gene-induction associated with survival in B cells (9). TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF family of type II membrane proteins, induces apoptosis upon binding to death receptors DR4 and DR5 (12).…”

mentioning

confidence: 93%

“…Inhibition of growth or induction of apoptosis are major therapeutic effects of IFN-α/β in cancer (6) and, likewise, one of the proposed immunoregulatory mechanisms of IFN-β therapy in RRMS is the induction of apoptosis in immune cells involved in pathogenesis (3,7). IFN-α/β has opposing biological effects on different leukocyte subsets, namely, induction of apoptosis in monocytes and enhanced survival in T and B cells (8,9). The molecular responses to IFN-β are initiated when it binds to its receptor, leading to activation of the receptor-associated kinases JAK1 and TYK2 and also to the activation of additional kinases (PI3K/Akt, p38, ERK, and JNK), and then to the activation of several transcription factors (TFs), including STATs 1-6, NF-κB, AP-1, IRF1, IRF4, IRF8, and PU1 (8).…”

mentioning

confidence: 99%

“…The molecular responses to IFN-β are initiated when it binds to its receptor, leading to activation of the receptor-associated kinases JAK1 and TYK2 and also to the activation of additional kinases (PI3K/Akt, p38, ERK, and JNK), and then to the activation of several transcription factors (TFs), including STATs 1-6, NF-κB, AP-1, IRF1, IRF4, IRF8, and PU1 (8). Activation of STAT3, STAT5, and NF-κΒ are linked to increased cell survival, whereas activation of STAT1 in general, NF-κΒ under certain conditions, and p38 especially in hematopoietic cells, lead to apoptosis (6,(9)(10)(11). We hypothesized that differential activation of these various signaling proteins could help to explain cell type-specific induction of apoptosis in response to IFN-α/β (9).…”

mentioning

confidence: 99%

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The role of cell type-specific responses in IFN-β therapy of multiple sclerosis

Zula

Green

Ransohoff

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The mechanism of IFN-β therapy in relapsing-remitting multiple sclerosis (RRMS) is not well understood, but induction of apoptosis in specific leukocyte subsets is likely to be important. Enhanced expression of TNFSF10 or TNF-related apoptosis-inducing ligand (TRAIL) mRNA in unseparated leukocytes has been put forward as a therapeutic response marker, but it is unclear which leukocyte subsets express TRAIL. We investigated the basis of TRAIL expression in response to IFN-β by studying activation of STATs 1, 3, and 5, p38 MAPK, and NF-κB in different leukocyte subsets of patients with RRMS. Monocytes, B cells, and T cells showed substantial differences in the activation of p38 and the STATs in response to i.m. injection of IFN-β1a or stimulation in vitro. Induction of cellsurface TRAIL, analyzed in nine leukocyte subsets, was observed only on monocytes and granulocytes and correlated with the activation of p38 and/or NF-κB in these subsets only, in agreement with previous work in fibroblasts showing that the induction of TRAIL in response to IFN-β depends on the activation of p38 and NF-κB as well as STATs 1 and 2. We propose that, in myeloid cells, the differential activation of p38 and NF-κB and induction of TRAIL, which sensitizes cells to apoptosis, can help to explain differences in responsiveness to IFN-β therapy among patients with RRMS and, furthermore, that such differential patterns of activation and expression may also be important in understanding the therapeutic responses to IFN-α/β in hepatitis and cancer.humans | phosphoproteins | signal transduction | flow cytometry

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Section: Resultssupporting

confidence: 86%

Section: Resultsmentioning

confidence: 80%

mentioning

confidence: 93%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The role of cell type-specific responses in IFN-β therapy of multiple sclerosis

Zula

Green

Ransohoff

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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miR‐155 as a multiple sclerosis–relevant regulator of myeloid cell polarization

Moore

Rao

Durafourt

et al. 2013

Annals of Neurology

197

159

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Our results demonstrate that miR-155 regulates proinflammatory responses in both blood-derived and central nervous system (CNS)-resident myeloid cells, in addition to impacting subsequent adaptive immune responses. Differential miRNA expression may therefore provide insight into mechanisms responsible for distinct phenotypic and functional properties of myeloid cells, thus impacting their ability to influence CNS injury and repair.

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Type I and III interferons enhance IL‐10R expression on human monocytes and macrophages, resulting in IL‐10‐mediated suppression of TLR‐induced IL‐12

Liu¹,

Janssen²,

Boonstra

2012

Eur J Immunol

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Currently, only about 30-50% of chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) patients respond to IFN-based therapy. It has been suggested that IL-10 is involved in suppressing the activity of type I IFNs on antigen-presenting cells (APCs). However, the interaction between type I IFNs and IL-10 is still not clear. Here we report that IFN-α priming upregulated the expression of IL-10R1 on monocytes, and subsequently IL-10 induced a higher level of STAT3 phosphorylation in IFN-primed cells. This indicates that IFN-α increased the sensitivity of monocytes to IL-10, and as a result, TLR-induced IL-12p70 by IFN-pretreated cells was suppressed. Interestingly, both IFN-β and IL-29, a member of the type III IFN family, comparably sensitized monocytes and macrophages to IL-10 stimulation, indicating a general effect of IFN on the activity of IL-10 in APCs. In summary, we demonstrate that one of the consequences of priming human APCs with IFN is to promote the cells' sensitivity to IL-10, which leads to the inhibition of TLR-induced IL-12p70 production. Therefore, type I and III IFNs induce a suboptimal activation of immune cells. These findings are relevant for the development of strategies to further improve IFN-based therapy for patients with multiple sclerosis or viral hepatitis.

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Major Differences in the Responses of Primary Human Leukocyte Subsets to IFN-β

Cited by 65 publications

References 58 publications

The role of cell type-specific responses in IFN-β therapy of multiple sclerosis

The role of cell type-specific responses in IFN-β therapy of multiple sclerosis

miR‐155 as a multiple sclerosis–relevant regulator of myeloid cell polarization

Type I and III interferons enhance IL‐10R expression on human monocytes and macrophages, resulting in IL‐10‐mediated suppression of TLR‐induced IL‐12

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