Cytokine mRNA expression in the liver of patients with primary biliary cirrhosis (PBC) and chronic hepatitis B (CHB)

Abstract

SUMMARYThe expression of cytokine mRNA species was determined in liver biopsies from six normal subjects, 18 patients with PBC and 14 patients with hepatitis B e antigen (HBeAg)-positive CHB using a reverse transcriptase-polymerase chain reaction (RT-PCR) technique. cDNA, obtained by reverse transcription using oligo d(T) primers, was amplified by PCR using primers specific for the coding region of seven different cytokines (IL-1, IL-2, IL-4, IL-5, IL-6, interferon-gamma (IFN-°), tumour necrosis factoralpha (TNF-®)). The abundance of some cytokines (IL-2, IL-4, IL-5 and IFN-°) was also estimated by semiquantitative RT-PCR, using as standards dilutions of synthetic cytokine mRNA transcripts, that could be distinguished electrophoretically from respective native cytokine mRNAs. Hepatic inflammation was assessed by a semiquantitative histologic score and by amplification of mRNA for T cell receptor (TCR)-®. mRNAs for IL-1 and IL-6 were detected in only one control liver. In CHB, mRNAs for IL-1, IL-2, IL-4, IL-5 and IFN-°were detected in 43%, 60%, 80%, 20%, and 54% of biopsies, respectively. mRNA for IFN-°and IL-4, but not IL-1, tended to be associated with severe inflammation. In five biopsies semiquantitative analyses revealed increased levels of mRNA for TCR-® and, when transcripts were detectable, high levels of mRNA for IFN-°and IL-4. In PBC, mRNA for IFN-°was detected in 60% of biopsies, but no mRNAs for IL-1, IL-2, IL-4, IL-5, or IL-6, or for TNF-®, were detected. Semiquantitative analyses revealed that absolute levels of mRNA for IFN-°tended to correlate with the severity of hepatic inflammation. The results suggest that: (i) there may be fundamental differences in the roles that cytokines play in the hepatic inflammatory processes of PBC and CHB; and (ii) while hepatic IFN-°mRNA expression is not specific for PBC, IFN-°may play a prominent role in the immunopathogenesis of PBC.

Altered Monocyte Responses to Defined TLR Ligands in Patients With Primary Biliary Cirrhosis *

“…27 Defects may be present in 1 or more of these pathways in PBC patients that could be the basis of enhanced cytokine synthesis. Furthermore, the monocyte PAMP-induced cytokine production observed in our study appears compatible with previously obtained data [28][29][30][31][32] that implicate a significant role of Th-1 cytokines in the pathogenesis of PBC. We note, however, that Th-2 cytokines, such as IL-5, IL-6, and IL-10, also have been detected in PBC livers, 29,31 indicating that both Th-1 and Th-2 cytokines, possibly during different stages of the disease, might be involved in the pathogenesis of PBC.…”

Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis

“…Th1 cells are important for the pathogenesis of various autoimmune diseases, 29 whereas Th2 cells contribute to allergic diseases. 30 According to several previous reports, in the liver of PBC, Th1 was found to be dominant [3][4][5]31 or present in combination with Th2. 32 The cytokines IFN-g and IL-4, IL-6 or IL-10 are hallmarks of Th1 and Th2, respectively.…”

“…This technique pinpointed the target sites for specimen collection and allowed us to investigate the gene expression of cytokines and TLRs in each specific liver area. Although several studies have analyzed cytokine expression in liver of PBC patients, [1][2][3][4][5][6][7] this is the first study to measure the steady-state expression levels of cytokines and TLRs in early stages of PBC within separate liver microenvironments of the portal tract and liver parenchyma. Th1 cells are important for the pathogenesis of various autoimmune diseases, 29 whereas Th2 cells contribute to allergic diseases.…”

“…Since cytokines are pivotal factors regulating the inflammatory responses prevalent in many autoimmune disorders, the roles of cytokines have been previously investigated in the pathogenesis of PBC. [1][2][3][4][5][6][7] Despite these inquiries, the significance of each cytokine in the microenvironment of the liver remains elusive. Furthermore, several reports suggest that infectious agents may also be involved in the pathogenesis of PBC.…”

Eosinophils and primary biliary cirrhosis—Stoking the fire?

“…9 Although both Th1 and Th2 cells are found in the liver of patients with PBC, 10 assessment of the cytokine profile in the liver of patients with PBC gives conflicting results: Martinez et al 11 found evidence of Th2-type cytokines with increased messenger RNA for IL-5 when compared with livers from patients with autoimmune hepatitis, whereas Harada et al 12 found evidence to support a Th1 profile, with increased messenger RNA for IL-4, although interferon-␥ was seen around damaged portal tracks. Shindo et al 13 were able to detect in the liver of PBC patients messenger RNA for interferon-␥ but not for IL-1, 2, 4, 5, or 6. Dienes et al 14 also found evidence for a Th1 predominance.…”