Type I IFN Regulation Of IL-10 Is Detrimental To Endothelial Cell Differentiation and May Enhance Cardiovascular Risk In Systemic Lupus Erythematosus

J. Michelle Kahlenberg¹, Alyssa Cates², Victoria Holden³, Carolyne K. Smith⁴ and Mariana J. Kaplan⁵, ¹Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI, ²Internal Medicine, Rheumatology, University of Michigan, Ann Arbor, MI, ³Pathology, University of Michigan, Ann Arbor, MI, ⁴Rheumatology and Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, ⁵Systemic Autoimmunity Branch, National Institutes of Health/NIAMS, Bethesda, MD

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Cardiovascular disease, endothelial cells, interferons and interleukins (IL)

Session Information

Title: Systemic Lupus Erythematosus - Human Etiology and Pathogenesis: Mechanisms and Biomarkers

Session Type: Abstract Submissions (ACR)

Background/Purpose: Systemic Lupus Erythematosus (SLE) is a heterogeneous disease resulting in organ damage and an elevated risk of cardiovascular disease (CVD). Previous reports have suggested that type-I interferon (IFN)-mediated repression of IL-1β and activation of IL-18 are important pathways leading to endothelial dysfunction and CVD in lupus patients. While typically viewed as anti-inflammatory, Interleukin-10 (IL-10) levels are elevated in SLE patients, where they may play pathogenic roles related to immune activation of B cell responses. Furthermore, IL-10 induces transcriptional repression of IL-1β synthesis. This study explores whether IL-10 has a detrimental effect on endothelial progenitor cell (EPC) differentiation and function and whether it may play a role in type I IFN-mediated repression of IL-1β in SLE with secondary detrimental effects on neoangiogenesis.

Methods: Human and murine control and lupus EPCs were induced to differentiate into mature endothelial cells (ECs) in the presence or absence of graded concentrations of recombinant IL-10 or a neutralizing Ab to this cytokine. IL-10 deficient mice were used to assess the role of this cytokine in type I IFN-mediated inhibition of neoangiogenesis using an in vivo Matrigel plug assay.

Results: In murine EPC/CAC cultures, the inhibitory effects of IFN-α on EPC/CAC differentiation were abrogated using an anti-IL-10 neutralizing antibody or cultures from IL-10 -/- mice. Further, the inhibitory effects of IFN-α on neoangiogensis in vivo were abrogated in IL-10 -/- mice. In human EPC cultures, anti-IL-10 neutralizing antibodies did not significantly impact the differentiation of control cells, but improved the differentiation of SLE EPCs into mature ECs. Conversely, addition of recombinant IL-10 was detrimental to EPC growth and differentiation and this was enhanced by type I IFNs in both control and SLE cultures. Upregulation of IL-10 was detected following type I IFN treatment of early EPC cultures , while both recombinant IL-10 and IFN-α resulted in enhanced repression of IL-1β in these cells.

Conclusion: These results indicate that IL-10 is detrimental to vasculogenesis and is an important intermediary in the IFN-α-mediated repression of proangiogenic IL-1β previously observed in these cells. As type I IFNs induce IL-10 synthesis, these results indicate that elevated levels of IL-10 in SLE patients may be associated with cardiovascular risk .

Disclosure:

J. M. Kahlenberg,
None;

A. Cates,
None;

V. Holden,
None;

C. K. Smith,
None;

M. J. Kaplan,
None.

« Back to 2013 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/type-i-ifn-regulation-of-il-10-is-detrimental-to-endothelial-cell-differentiation-and-may-enhance-cardiovascular-risk-in-systemic-lupus-erythematosus/