Interleukin-27 Is a Potential Rescue Therapy for Acute Severe Colitis Through Interleukin-10–Dependent, T-Cell–Independent Attenuation of Colonic Mucosal Innate Immune Responses

Mairi H. McLean, Caroline Andrews, Miranda L. Hanson, Walter A. Baseler, Miriam R. Anver, Emilee Senkevitch, Aleksandra K. Staniszewska , Luke C. Davies, Julie Hixon, Wenqeng Li, Wei Shen, Lothar Steidler, Scott K. Durum

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Abstract

Background; IBD patients with acute severe colitis face systemic anti-TNF biologic rescue therapy or colectomy, if treatment with intravenous steroids fail. Interleukin (IL)-27 is a cytokine with an immunosuppressive role in adaptive immune responses. However, the IL-27 receptor complex is also expressed on innate immune cells, and there is evidence that IL-27 can impact the function of innate cell subsets, although this particular functionality in vivo is not understood. Our aim was to define the efficacy of IL-27 in acute severe colitis and characterize novel IL-27 driven mechanisms of immunosuppression in the colonic mucosa.


Methods; We assessed oral delivery of Lactococcus lactis expressing an IL-27 hyperkine on the innate immune response in vivo in a genetically intact, non-infective acute murine colitis model induced by intra-rectal instillation of 2,4,6-Trinitrobenzenesulfonic acid in SJL/J mice.


Results; IL-27 attenuates acute severe colitis through reduction of colonic mucosal neutrophil infiltrate associated with a decreased CXC chemokine gradient. This suppression was T cell-independent and IL- 10-dependent, initially featuring enhanced mucosal IL-10. IL-27 was associated with a reduction in colonic pro-inflammatory cytokines and induced a multifocal strong positive nuclear expression of phosphorylated STAT-1 in mucosal epithelial cells.


Conclusion; We have defined novel mechanisms of IL-27 immunosuppression towards colonic innate immune responses in vivo. Mucosal delivery of IL-27 has translational potential as a novel therapeutic for IBD and is a future mucosal directed rescue therapy in acute severe inflammatory bowel disease.
Original languageEnglish
Pages (from-to)1983-1995
Number of pages12
JournalInflammatory Bowel Diseases
Volume23
Issue number11
Early online date9 Oct 2017
DOIs
Publication statusPublished - Nov 2017

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Interleukin-27
Mucosal Immunity
Interleukins
Colitis
Innate Immunity
Therapeutics
Interleukin-10
Immunosuppression
Interleukin Receptors
Trinitrobenzenesulfonic Acid
Rectal Administration
Cytokines
CXC Chemokines
Lactococcus lactis
Biological Therapy
Colectomy
Adaptive Immunity
Immunosuppressive Agents
Inflammatory Bowel Diseases
Mucous Membrane

Keywords

  • interleukin-27
  • cytokine
  • IBD
  • colitis

Cite this

Interleukin-27 Is a Potential Rescue Therapy for Acute Severe Colitis Through Interleukin-10–Dependent, T-Cell–Independent Attenuation of Colonic Mucosal Innate Immune Responses. / McLean, Mairi H.; Andrews, Caroline; Hanson, Miranda L.; Baseler, Walter A.; Anver, Miriam R.; Senkevitch, Emilee; Staniszewska , Aleksandra K.; Davies, Luke C.; Hixon, Julie; Li, Wenqeng; Shen, Wei; Steidler, Lothar; Durum, Scott K.

In: Inflammatory Bowel Diseases, Vol. 23, No. 11, 11.2017, p. 1983-1995.

Research output: Contribution to journalArticle

McLean, MH, Andrews, C, Hanson, ML, Baseler, WA, Anver, MR, Senkevitch, E, Staniszewska , AK, Davies, LC, Hixon, J, Li, W, Shen, W, Steidler, L & Durum, SK 2017, 'Interleukin-27 Is a Potential Rescue Therapy for Acute Severe Colitis Through Interleukin-10–Dependent, T-Cell–Independent Attenuation of Colonic Mucosal Innate Immune Responses', Inflammatory Bowel Diseases, vol. 23, no. 11, pp. 1983-1995. https://doi.org/10.1097/MIB.0000000000001274
McLean, Mairi H. ; Andrews, Caroline ; Hanson, Miranda L. ; Baseler, Walter A. ; Anver, Miriam R. ; Senkevitch, Emilee ; Staniszewska , Aleksandra K. ; Davies, Luke C. ; Hixon, Julie ; Li, Wenqeng ; Shen, Wei ; Steidler, Lothar ; Durum, Scott K. / Interleukin-27 Is a Potential Rescue Therapy for Acute Severe Colitis Through Interleukin-10–Dependent, T-Cell–Independent Attenuation of Colonic Mucosal Innate Immune Responses. In: Inflammatory Bowel Diseases. 2017 ; Vol. 23, No. 11. pp. 1983-1995.
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title = "Interleukin-27 Is a Potential Rescue Therapy for Acute Severe Colitis Through Interleukin-10–Dependent, T-Cell–Independent Attenuation of Colonic Mucosal Innate Immune Responses",
abstract = "Background; IBD patients with acute severe colitis face systemic anti-TNF biologic rescue therapy or colectomy, if treatment with intravenous steroids fail. Interleukin (IL)-27 is a cytokine with an immunosuppressive role in adaptive immune responses. However, the IL-27 receptor complex is also expressed on innate immune cells, and there is evidence that IL-27 can impact the function of innate cell subsets, although this particular functionality in vivo is not understood. Our aim was to define the efficacy of IL-27 in acute severe colitis and characterize novel IL-27 driven mechanisms of immunosuppression in the colonic mucosa.Methods; We assessed oral delivery of Lactococcus lactis expressing an IL-27 hyperkine on the innate immune response in vivo in a genetically intact, non-infective acute murine colitis model induced by intra-rectal instillation of 2,4,6-Trinitrobenzenesulfonic acid in SJL/J mice.Results; IL-27 attenuates acute severe colitis through reduction of colonic mucosal neutrophil infiltrate associated with a decreased CXC chemokine gradient. This suppression was T cell-independent and IL- 10-dependent, initially featuring enhanced mucosal IL-10. IL-27 was associated with a reduction in colonic pro-inflammatory cytokines and induced a multifocal strong positive nuclear expression of phosphorylated STAT-1 in mucosal epithelial cells.Conclusion; We have defined novel mechanisms of IL-27 immunosuppression towards colonic innate immune responses in vivo. Mucosal delivery of IL-27 has translational potential as a novel therapeutic for IBD and is a future mucosal directed rescue therapy in acute severe inflammatory bowel disease.",
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author = "McLean, {Mairi H.} and Caroline Andrews and Hanson, {Miranda L.} and Baseler, {Walter A.} and Anver, {Miriam R.} and Emilee Senkevitch and Staniszewska, {Aleksandra K.} and Davies, {Luke C.} and Julie Hixon and Wenqeng Li and Wei Shen and Lothar Steidler and Durum, {Scott K.}",
note = "This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, as well as a fellowship funded by Crohn’s and Colitis Foundation of America (MHM) and a grant from the Broad Medical Research Foundation. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E (MRA). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.",
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T1 - Interleukin-27 Is a Potential Rescue Therapy for Acute Severe Colitis Through Interleukin-10–Dependent, T-Cell–Independent Attenuation of Colonic Mucosal Innate Immune Responses

AU - McLean, Mairi H.

AU - Andrews, Caroline

AU - Hanson, Miranda L.

AU - Baseler, Walter A.

AU - Anver, Miriam R.

AU - Senkevitch, Emilee

AU - Staniszewska , Aleksandra K.

AU - Davies, Luke C.

AU - Hixon, Julie

AU - Li, Wenqeng

AU - Shen, Wei

AU - Steidler, Lothar

AU - Durum, Scott K.

N1 - This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, as well as a fellowship funded by Crohn’s and Colitis Foundation of America (MHM) and a grant from the Broad Medical Research Foundation. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E (MRA). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

PY - 2017/11

Y1 - 2017/11

N2 - Background; IBD patients with acute severe colitis face systemic anti-TNF biologic rescue therapy or colectomy, if treatment with intravenous steroids fail. Interleukin (IL)-27 is a cytokine with an immunosuppressive role in adaptive immune responses. However, the IL-27 receptor complex is also expressed on innate immune cells, and there is evidence that IL-27 can impact the function of innate cell subsets, although this particular functionality in vivo is not understood. Our aim was to define the efficacy of IL-27 in acute severe colitis and characterize novel IL-27 driven mechanisms of immunosuppression in the colonic mucosa.Methods; We assessed oral delivery of Lactococcus lactis expressing an IL-27 hyperkine on the innate immune response in vivo in a genetically intact, non-infective acute murine colitis model induced by intra-rectal instillation of 2,4,6-Trinitrobenzenesulfonic acid in SJL/J mice.Results; IL-27 attenuates acute severe colitis through reduction of colonic mucosal neutrophil infiltrate associated with a decreased CXC chemokine gradient. This suppression was T cell-independent and IL- 10-dependent, initially featuring enhanced mucosal IL-10. IL-27 was associated with a reduction in colonic pro-inflammatory cytokines and induced a multifocal strong positive nuclear expression of phosphorylated STAT-1 in mucosal epithelial cells.Conclusion; We have defined novel mechanisms of IL-27 immunosuppression towards colonic innate immune responses in vivo. Mucosal delivery of IL-27 has translational potential as a novel therapeutic for IBD and is a future mucosal directed rescue therapy in acute severe inflammatory bowel disease.

AB - Background; IBD patients with acute severe colitis face systemic anti-TNF biologic rescue therapy or colectomy, if treatment with intravenous steroids fail. Interleukin (IL)-27 is a cytokine with an immunosuppressive role in adaptive immune responses. However, the IL-27 receptor complex is also expressed on innate immune cells, and there is evidence that IL-27 can impact the function of innate cell subsets, although this particular functionality in vivo is not understood. Our aim was to define the efficacy of IL-27 in acute severe colitis and characterize novel IL-27 driven mechanisms of immunosuppression in the colonic mucosa.Methods; We assessed oral delivery of Lactococcus lactis expressing an IL-27 hyperkine on the innate immune response in vivo in a genetically intact, non-infective acute murine colitis model induced by intra-rectal instillation of 2,4,6-Trinitrobenzenesulfonic acid in SJL/J mice.Results; IL-27 attenuates acute severe colitis through reduction of colonic mucosal neutrophil infiltrate associated with a decreased CXC chemokine gradient. This suppression was T cell-independent and IL- 10-dependent, initially featuring enhanced mucosal IL-10. IL-27 was associated with a reduction in colonic pro-inflammatory cytokines and induced a multifocal strong positive nuclear expression of phosphorylated STAT-1 in mucosal epithelial cells.Conclusion; We have defined novel mechanisms of IL-27 immunosuppression towards colonic innate immune responses in vivo. Mucosal delivery of IL-27 has translational potential as a novel therapeutic for IBD and is a future mucosal directed rescue therapy in acute severe inflammatory bowel disease.

KW - interleukin-27

KW - cytokine

KW - IBD

KW - colitis

U2 - 10.1097/MIB.0000000000001274

DO - 10.1097/MIB.0000000000001274

M3 - Article

VL - 23

SP - 1983

EP - 1995

JO - Inflammatory Bowel Diseases

JF - Inflammatory Bowel Diseases

SN - 1078-0998

IS - 11

ER -