Endogenous IL-22 plays a dual role in arthritis: regulation of established arthritis via IFN-γ responses.

Abstract

OBJECTIVE:

IL-22 is elevated in patients with inflammatory arthritis and correlates with disease activity. IL-22 deficient mice have reduced incidence of arthritis. Recombinant IL-22 restrains progression of arthritis via increase in IL-10 responses when administered prior to onset of arthritis. These findings imply a possible dual role of IL-22 in inflammatory arthritis depending on the phase of arthritis. Experiments outlined here were designed to elucidate the contribution of endogenous IL-22 before and after the onset of arthritis.

METHODS:

Collagen induced arthritis (CIA) was induced in DBA1 or IFN-γ deficient mice following immunization with collagen and complete Freund's adjuvant. Anti-IL-22 antibody or isotype control were administered prior to or after onset of arthritis and disease progression assessed by clinical scoring and histopathology. IL-22, IL-17 and IFN-γ responses were measured by ELISA and flowcytometry. Anti-collagen antibody responses were analyzed by ELISA. Expression of IL-22R1 in CD4+ cells was elucidated by flowcytometry and real time PCR.

RESULTS:

Collagen specific IL-22 responses were expanded during arthritis and IL-22 producing cells were discrete from IL-17 or IFN-γ producing cells. Neutralization of IL-22 after onset of arthritis resulted in significant increase in Th1 responses and significantly reduced severity of arthritis. CD4+ cells from arthritic mice showed increased surface expression of IL-22R1. In vitro, CD4+T cells cultured with antigen presenting cells in the presence or absence of IL-22 suppressed or induced IFN-γ, respectively. The protective effect of anti-IL-22 was reversed in IFN-γ deficient mice. Moreover, administration of anti-IL-22 prior to onset of arthritis augmented arthritis severity.

CONCLUSION:

We show for the first time that IL-22 plays a dual role: protective prior to the onset of arthritis and pathogenic after onset of arthritis. The pathogenic effect of IL-22 is dependent on suppression of IFN-γ responses. IL-17 responses remained unchanged with the administration of anti-IL22 antibody. IL-22R1 is upregulated on CD4+T cells during arthritis and regulates IFN-γ in T cells.

• Authors: Shivali Justa, Xiaoqun Zhou, Sujata Sarkar
• Journal: PloS one (PLoS One) Vol. 9 Issue 3 Pg. e93279 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24676270 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Neutralizing
• Interleukin-17
• Interleukins
• Receptors, Interleukin
• interleukin-22 receptor
• Interferon-gamma
• Collagen
• Freund's Adjuvant
• interleukin-22

Topics

• Animals
• Antibodies, Neutralizing (pharmacology)
• Arthritis, Experimental (chemically induced, genetics, immunology, pathology)
• Collagen
• Female
• Freund's Adjuvant
• Gene Expression Regulation (immunology)
• Interferon-gamma (deficiency, genetics, immunology)
• Interleukin-17 (genetics, immunology)
• Interleukins (antagonists & inhibitors, genetics, immunology)
• Male
• Mice
• Mice, Inbred DBA
• Mice, Knockout
• Receptors, Interleukin (genetics, immunology)
• Severity of Illness Index
• Signal Transduction
• Th1 Cells (immunology, pathology)