Interleukin-15 as a potential regulator of the innate immune response

Carson, William E.; Caligiuri, Michael A.

doi:10.1590/s0100-879x1998000100001

Cited by 30 publications

(14 citation statements)

References 26 publications

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“…I nterleukin-15 is a potent growth factor for T and B lymphocytes and NK cells (1)(2)(3)(4)(5)(6)(7)(8), a chemoattractant for T cells (9), and an activator of the cytolytic program in T and NK cells (10,11). Although IL-15 shares many biological activities with IL-2, there is increasing appreciation of a large spectrum of activities in which IL-2 and IL-15 differ (8,(12)(13)(14)(15).…”

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confidence: 99%

The IL-15Rα Chain Signals Through Association with Syk in Human B Cells

Bulanova

Budagian

Pohl

et al. 2001

The Journal of Immunology

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The α-chain of the IL-15R (IL-15Rα) serves as the specific, high-affinity receptor for IL-15. It is expressed by lymphoid and nonlymphoid cells, including B cell lymphoma lines. In this study, we have further explored IL-15Rα-mediated signaling in activated primary B cells and in Raji cells, a human B-lymphoblastoid cell line which expresses the IL-15Rα and IL-2Rγ chains, but lacks the IL-2Rβ chain. Stimulation of Raji cells with IL-15 induces their proliferation and rescues them from C2-ceramide-induced apoptosis. By immunoprecipitation and Western blotting, we show that treatment of Raji cells and activated primary B cells with IL-15 induces coprecipitation of Syk kinase with the IL-15Rα chain. Upon association, the activated Syk kinase phosphorylates the IL-15Rα chain as well as phospholipase Cγ, which coprecipitates with Syk. Furthermore, transfection of Raji cells with stem-loop Syk antisense oligonucleotides prevents IL-15Rα and phospholipase Cγ phosphorylation as well as the inhibition of apoptosis by IL-15. Mutation of a defined region of the intracellular signaling portion of IL-15Rα (Tyr227) abrogates both the IL-15Rα/Syk association and IL-15Rα phosphorylation. Taken together, this suggests that Syk kinase physically and functionally associates with the IL-15Rα chain in B cells and that Syk plays a key role in mediating IL-15-induced signal transduction, thus accounting for the distinct functional consequences of IL-15 vs IL-2 binding to B cells.

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confidence: 99%

The IL-15Rα Chain Signals Through Association with Syk in Human B Cells

Bulanova

Budagian

Pohl

et al. 2001

The Journal of Immunology

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“…These observations strongly suggest a synergistic mechanism of action of IL-12 with IL-15 and/or IL-18. Endogenous IL-15 produced by LPS-activated monocytes works in concert with IL-12 for optimal IFN-γ production by NK cells [43]. Several studies have shown that IL-18 responsiveness is dependent upon IL-12 and vice versa for T cells [44], [45].…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of NK Cell-Macrophage Bacillus anthracis Crosstalk: A Balance between Stimulation by Spores and Differential Disruption by Toxins

et al. 2012

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NK cells are important immune effectors for preventing microbial invasion and dissemination, through natural cytotoxicity and cytokine secretion. Bacillus anthracis spores can efficiently drive IFN-γ production by NK cells. The present study provides insights into the mechanisms of cytokine and cellular signaling that underlie the process of NK-cell activation by B. anthracis and the bacterial strategies to subvert and evade this response. Infection with non-toxigenic encapsulated B. anthracis induced recruitment of NK cells and macrophages into the mouse draining lymph node. Production of edema (ET) or lethal (LT) toxin during infection impaired this cellular recruitment. NK cell depletion led to accelerated systemic bacterial dissemination. IFN-γ production by NK cells in response to B. anthracis spores was: i) contact-dependent through RAE-1-NKG2D interaction with macrophages; ii) IL-12, IL-18, and IL-15-dependent, where IL-12 played a key role and regulated both NK cell and macrophage activation; and iii) required IL-18 for only an initial short time window. B. anthracis toxins subverted both NK cell essential functions. ET and LT disrupted IFN-γ production through different mechanisms. LT acted both on macrophages and NK cells, whereas ET mainly affected macrophages and did not alter NK cell capacity of IFN-γ secretion. In contrast, ET and LT inhibited the natural cytotoxicity function of NK cells, both in vitro and in vivo. The subverting action of ET thus led to dissociation in NK cell function and blocked natural cytotoxicity without affecting IFN-γ secretion. The high efficiency of this process stresses the impact that this toxin may exert in anthrax pathogenesis, and highlights a potential usefulness for controlling excessive cytotoxic responses in immunopathological diseases. Our findings therefore exemplify the delicate balance between bacterial stimulation and evasion strategies. This highlights the potential implication of the crosstalk between host innate defences and B. anthracis in initial anthrax control mechanisms.

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“…Since the simultaneous neutralization of IL-12 and IL-18 did not lead to a complete inhibition of IFN-␥ release by PPVO, it is likely that additional mechanisms might be involved. It is known that also other cytokines (e.g., IL-15, TNF-␣, and IL-1␤) act synergistically with IL-12 on IFN-␥ release (5).…”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory Effects of Inactivated Parapoxvirus Ovis (Orf Virus) on Human Peripheral Immune Cells: Induction of Cytokine Secretion in Monocytes and Th1-Like Cells

Friebe

Siegling

Friederichs

et al. 2004

J Virol

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Inactivated parapoxvirus ovis (Orf virus;Parapoxvirus ovis (Orf virus; PPVO) is a member of the poxvirus family and causes pustular skin lesions in sheep, goats, and humans (20). The family of poxviruses consists of large DNA viruses with strong immunogenic properties. To evade the host immune defense, poxviruses utilize a variety of immunomodulatory cellular proteins, which enable them to replicate in spite of an active immune response (1,16,17,28). Such proteins have been described for PPVO; these include a viral interleukin 10 (IL-10) homologue (11, 12), a granulocyte-macrophage colony-stimulating factor, an IL-2-inhibiting protein (8), and the product of a gene with homology to the vaccinia virus E3L gene, which counteracts interferon-induced cell resistance (18,19,21,30).The immunostimulating and modulating capacities made PPVO an interesting candidate for new antiviral strategies (36). The immunomodulatory properties of the virus could be used by means of a noninfectious preparation of inactivated PPVO to influence the clinical course of other viral infections. Thus, inactivated PPVO showed strong effects in several animal models for acute and chronic virus infections. It was effective in a guinea pig model for genital herpes disease and in a transgenic mouse model for human hepatitis B virus (HBV). In HBVtransgenic mice, PPVO led to a reduction in virus replication that was not associated with the destruction of liver cells. Furthermore, PPVO was able to reduce lethality in mice infected with herpes simplex virus. This effect also was not accompanied by a tissue-damaging inflammatory response or other side effects (36).Investigations of the cytokine expression profiles of animals treated with PPVO implicate gamma interferon (IFN-␥) as a key mediator of the PPVO-mediated activity against HBV and herpes simplex virus. Thus, the application of PPVO first led to the release of Th1-inducing or effector cytokines, such as IL-12, IL-18, and IFN-␥. The neutralization of IFN-␥ by antibodies could abolish antiviral effects in vivo. The induction of type 1 cytokines was followed by the secretion of anti-inflammatory cytokines, such as IL-4 (36). These findings indicate the induction of a limited immune response and offer an explanation for the good tolerability of the preparation in animals. The immunomodulatory properties of PPVO might be responsible for the observed antiviral effects and might contribute to the absence of systemic side effects and the absence of tissue injury that are observed after the direct administration of Th1-inducing or effector cytokines.The aim of this study was to investigate whether the effects of PPVO can be determined under controlled conditions in human immune cells. In the work presented, we evaluated the cytokine secretion of peripheral blood cells, especially IFN-␥, which has been proved in animal models to be an important factor in transducing antiviral effects. In addition, we evaluated the mechanisms that mediate the effects of PPVO.

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Interleukin-15 as a potential regulator of the innate immune response

Cited by 30 publications

References 26 publications

The IL-15Rα Chain Signals Through Association with Syk in Human B Cells

The IL-15Rα Chain Signals Through Association with Syk in Human B Cells

Mechanisms of NK Cell-Macrophage Bacillus anthracis Crosstalk: A Balance between Stimulation by Spores and Differential Disruption by Toxins

Immunomodulatory Effects of Inactivated Parapoxvirus Ovis (Orf Virus) on Human Peripheral Immune Cells: Induction of Cytokine Secretion in Monocytes and Th1-Like Cells

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