Anti-Inflammatory Role of Interleukin-15 in Crohnʼs Disease

Silva, Manuel A.; Menezes, José; Deslandres, Colette; Seidman, Ernest G.

doi:10.1097/01.mib.0000160804.52072.6a

Cited by 17 publications

(17 citation statements)

References 49 publications

(111 reference statements)

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“…In this approximation, we tested a combination of phorbol 12-myristate 13-acetate and ionomycin (PMA/IO). PMA/IO exposure is a commonly used procedure for the activation of T cells and for the simulation of inflammatory conditions in human colonic explants, since PMA/IO act as potent inducers of T h 1-type cytokines IL-2 and IFN-c, which are found upregulated in inflammatory bowel diseases (Niedel et al 1983;Silva et al 2005). The analysis of the data in our experiments confirmed that PMA/IO provoked an inflammation-like pattern.…”

Section: Discussionsupporting

confidence: 78%

Lactobacillus paracasei and Lactobacillus plantarum strains downregulate proinflammatory genes in an ex vivo system of cultured human colonic mucosa

et al. 2012

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Significant health benefits have been demonstrated for certain probiotic strains through intervention studies; however, there is a shortage of experimental evidence relative to the mechanisms of action. Here, noninvasive experimental procedure based on a colon organ culture system has been used that, in contrast to most experimental in vitro models reported, can preserve natural immunohistochemical features of the human mucosa. This system has been used to test whether commensal lactobacilli (Lactobacillus paracasei BL23, Lactobacillus plantarum 299v and L. plantarum 299v (A -)) were able to hinder inflammation-like signals induced by phorbol 12-myristate 13-acetate (PMA)/ionomycin (IO). Whole genome microarrays have been applied to analyze expression differences, from which mRNA markers could be inferred to monitor the effect of putative probiotic strains under such conditions. Regarding the gene expression, PMA/IO treatment induced not only interleukin (IL)-2 and interferon gamma (IFN-c), as expected, but also other relevant genes related to immune response and inflammation, such as IL-17A, chemokine (C-X-C motif) ligand (CXCL) 9 and CXCL11. The ex vivo culturing did not modify the pattern of expression of those genes or others related to inflammation. Interestingly, this study demonstrated that lactobacilli downregulated those genes and triggered a global change of the transcriptional profile that indicated a clear homeostasis restoring effect and a decrease in signals produced by activated T cells.

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Section: Discussionsupporting

confidence: 78%

Lactobacillus paracasei and Lactobacillus plantarum strains downregulate proinflammatory genes in an ex vivo system of cultured human colonic mucosa

et al. 2012

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“…Such a tight negative regulation may serve to avoid deleterious consequences of excessive NK cell activation. Tight control of IL-15R␣ may be particularly important in humans who can show detectable levels of circulating IL-15, particularly in cases of inflammation and autoimmune pathologies (51,52). This contrasts with murine models where IL-15 remains mostly undetectable in the circulation.…”

Section: Discussionmentioning

confidence: 99%

A Programmed Switch from IL-15- to IL-2-Dependent Activation in Human NK Cells

Pillet

Bugault

Thèze

et al. 2009

The Journal of Immunology

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IL-2 and IL-15 differentially control the development, activation and proliferation of human NK cells, although they share common signal-transducing receptor chains CD122 and common γ. To explore this issue, we analyzed in detail the kinetics of cytokine receptor expression, cytokine binding, and signaling responses in human NK cells treated with common γ-chain family cytokines. We provide evidence for the sequential expression of IL-15Rα and IL-2Rα at the surface of cytokine-stimulated human NK cells, independent of the cytokine used for stimulation (IL-2, IL-15, or IL-7). Binding experiments confirmed the switch of high-affinity receptor from IL-15R to IL-2R between 18 and 48 h after stimulation. Consequently, phospho-STAT5 signaling responses to IL-15 were efficient in human NK cells pretreated with cytokines for 18 h, but were abolished at 48 h. Functional NK cell responses to IL-15, including IFN-γ secretion and CD107a expression, followed a similar pattern, indicating the physiological relevance of the cytokine receptor switch. Importantly, IL-15 complexed to soluble IL-15Rα preserved the capacity to activate cytokine-stimulated human NK cells at 48 h, suggesting that human NK cells remained competent for IL-15 trans-presentation, while they had become refractory to free diffusible IL-15. These findings define a common cytokine receptor expression program, which increases human NK cell sensitivity to free IL-15 in early activation and redirects responses toward IL-2 and trans-presented IL-15 at later stages. Such a program may prevent excessive human NK cell activation by effectors of innate immunity and regulate the transition between the innate and adaptive stages of immune responses.

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“…During the acute phase of the disease, CD4 ϩ T cells are the primary source of host IFN-␥ production (48), leading to immunopathology and ultimate death of the animal (11,26). CD4 ϩ T cells are known to play a primary role in number of autoimmune diseases such as inflammatory bowel disease, Crohn's disease, and experimental autoimmune encephalomyelitis (49)(50)(51). However, the importance of IL-15 in the elicitation of primary CD4 ϩ T cell response and subsequent effect on the pathogenesis of these diseases has not been reported.…”

Section: Discussionmentioning

confidence: 99%

Lack of IL-15 results in the suboptimal priming of CD4⁺T cell response against an intracellular parasite

Combe

Moretto

Schwartzman³

et al. 2006

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

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Anti-Inflammatory Role of Interleukin-15 in Crohnʼs Disease

Abstract: Our results suggest a possible anti-inflammatory role for IL-15 in CD. We postulate that its overexpression in CD potentially represents a protective mechanism against the exaggerated T(H)1 immune response.

Cited by 17 publications

References 49 publications

Lactobacillus paracasei and Lactobacillus plantarum strains downregulate proinflammatory genes in an ex vivo system of cultured human colonic mucosa

Lactobacillus paracasei and Lactobacillus plantarum strains downregulate proinflammatory genes in an ex vivo system of cultured human colonic mucosa

A Programmed Switch from IL-15- to IL-2-Dependent Activation in Human NK Cells

Lack of IL-15 results in the suboptimal priming of CD4⁺T cell response against an intracellular parasite

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Anti-Inflammatory Role of Interleukin-15 in Crohnʼs Disease

Abstract: Our results suggest a possible anti-inflammatory role for IL-15 in CD. We postulate that its overexpression in CD potentially represents a protective mechanism against the exaggerated T(H)1 immune response.

Cited by 17 publications

References 49 publications

Lactobacillus paracasei and Lactobacillus plantarum strains downregulate proinflammatory genes in an ex vivo system of cultured human colonic mucosa

Lactobacillus paracasei and Lactobacillus plantarum strains downregulate proinflammatory genes in an ex vivo system of cultured human colonic mucosa

A Programmed Switch from IL-15- to IL-2-Dependent Activation in Human NK Cells

Lack of IL-15 results in the suboptimal priming of CD4+T cell response against an intracellular parasite

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Lack of IL-15 results in the suboptimal priming of CD4⁺T cell response against an intracellular parasite