Hepatic IL-17 responses in human and murine primary biliary cirrhosis.
The emergence of new regulatory and pro-inflammatory immune cell subsets and cytokines dictates the need to re-examine the role of these subsets in various diseases involving the immune system. IL-17 has been recently identified as a key cytokine involved in numerous autoimmune processes. However, its role in liver autoimmune diseases remains unclear. Primary biliary cirrhosis (PBC) is characterized histologically by autoreactive CD4 and CD8 T cells surrounding damaged bile ducts. CD4(+) T cells are a major source of IL-17, which compose a distinct T helper subset (Th17). Thus we set out to determine the role of IL-17 in both human and a murine model of PBC in a liver-targeted manner. Our data demonstrate an increase in the frequency of IL-17(+) lymphocytic infiltration in liver tissues from PBC patients and those with other liver dysfunctions as compared to healthy livers. IL-2 receptor alpha knockout mice, a recently identified murine model of human PBC, also demonstrate marked aggregations of IL-17-positive cells within portal tracts and increased frequencies of Th17 cells in the liver compared to the periphery. Interestingly, CD4(+) T cells from livers of normal C57BL/6J mice also secreted higher levels of IL-17 relative to those from spleens, indicating a preferential induction of Th17 cells in liver tissues. Importantly, C57BL/6J cocultures of splenic CD4(+) T cells and liver non-parenchymal cells increased IL-17 production approximately 10-fold compared to T cells alone, suggesting a role of the liver microenvironment in Th17 induction in cases of liver autoimmunity and other liver inflammatory diseases.
Lan
Ruth Y Z
RY
Division of Rheumatology, Allergy and Clinical Immunology, Genome and Biomedical Sciences Facility, University of California at Davis, 451 East Health Sciences Drive, Suite 6510, Davis, CA 95616, USA.
Salunga
Thucydides L
TL
Tsuneyama
Koichi
K
Lian
Zhe-Xiong
ZX
Yang
Guo-Xiang
GX
Hsu
Willy
W
Moritoki
Yuki
Y
Ansari
Aftab A
AA
Kemper
Claudia
C
Price
Jeff
J
Atkinson
John P
JP
Coppel
Ross L
RL
Gershwin
M Eric
ME
D000367:Age Factors; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D020381:Interleukin-17 / Q000097:blood / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D007378:Interleukins / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008105:Liver Cirrhosis, Biliary / Q000276:immunology*; D008297:Male; D051916:Membrane Cofactor Protein / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013154:Spleen / Q000166:cytology / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000906:Antibodies; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D007378:Interleukins; D051916:Membrane Cofactor Protein; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma; D053804:Granzymes