Patients with chronic hepatitis C undergoing PEG-IFN+RBV therapy are at an increased risk for developing depression or aggravating pre-existing depression. Several mechanisms for the development of IFN-related depression have been suggested, however, no solid evidence for a common molecular mechanism has yet been proffered. At the same time, markers capable of predicting depression in CH-C patients are highly desirable as active depression during HCV treatment may jeopardize desired therapeutic outcomes and patients' health-related quality of life (Dan et al. 2006
; Younossi et al. 2007
Of note, in our study, we observed a significant baseline up-regulation of STAT4 in HCV patients with both a history of depression and new treatment-related depression. This gene has been shown to be intimately involved in the signaling cascade necessary for the activation and consequent pro-inflammatory signal cascade of Th1 type cells (Saraiva et al. 2009
A recent study on the effects of Th1/Th2 class cytokines on gene expression in cell culture found that Th2 class cytokines up-regulate the prepropeptide PDGF A chain (Lisak et al. 2007
). Indeed, in our study, both the presence of “Any Depression” as well as “Treatment-related Depression” resulted in significantly lower expression of PDGFA. These studies point toward a decrease in the Th2 class cytokine signaling as the potential mechanism of depression for these patients. In addition, for HCV patients with “Any Depression”, the PF4 gene was significantly down-regulated. The PF4 encodes for the soluble protein CXCL4, which is directly involved in the up-regulation of Th2 class of cytokines (Romagnani et al. 2005
; Mueller et al. 2008
). Other genes of interest associated with TRD include TRAF6 and PRKRIR, both of which are involved in inflammatory diseases and in the inflammatory signaling cascade (Cejas et al. 2010
; Kuenzel et al. 2010
), and PDGFA which encodes the prepropeptide PDGF A chain. PDGFA is specifically up-regulated by Th2 class cytokines (Lisak et al. 2007
). In our study, this gene was markedly suppressed, pointing to a decrease in the Th2 class cytokine signaling in HCV patients who develop depression. In fact, our data necessitate a closer examination of the pretreatment baseline levels of Th1 class and Th2 class cytokines in patients scheduled for IFN-α therapy, as interferon-induced depression may in fact involve a pre-existing imbalance in the host Th1/Th2 levels, rendering certain patients vulnerable to depression.
Our study also supports the potential role of TGF-β1 in IFN-related depression. TGF-β1 is mainly secreted by regulatory T cells such as type 1 regulatory T cells and T-helper type 3 cells (Th3) and is thought to be essential for the maintenance of immune homeostasis and for the suppression of autoimmunity (Groux et al. 1997
; Taylor et al. 2006
; Zhang et al. 2006
). TGF-β1 is known to not only promote T-helper type 2 cell (Th2) differentiation (Barral-Netto et al. 1992
) but also to exert a strong inhibitory effect on the production of pro-inflammatory cytokines such as interferons (IFNs), tumor necrosis factor (TNF-α), and IL-2 (Schmitt et al. 1994
; Prud'homme and Piccirillo 2000
) (). Recent studies indicate that, TGF-β1 plays a role in the development of depression by shifting the balance between the pro-inflammatory/anti-inflammatory cytokines seen in this disorder (Myint et al. 2005
; Lee and Kim 2006
). In fact, recent studies on MDD have shown that significantly lowered pretreatment TGF-β1 levels in the depressed patients increase following antidepressant therapy (Myint et al. 2005
). The decreased baseline levels of TGF-β1 seen within our cohort of HCV patients who ultimately developed depression during treatment, may well follow the same etiology as seen in patients with MDD. Importantly, TGF-β1 has been extensively studied within the context of liver disease, particularly in relation to inflammation and fibrosis (Wynn and Barron 2010
). However, little is known about its role within the context of PEG-IFN+RBV treatment of HCV and its associated side effects. The current study is the first to point to TGF-β1 as having a pivotal role in IFN-related depression.
Transforming growth factor-b (TGF-β) and its effects on a large group of secreted cytokines, with a wide range of functional properties.
Importantly, worldwide efforts in genome-wide profiling of the polymorphisms associated with MDD and antidepressant treatment outcomes produced only a handful of the candidate genes. Moreover, even in the largest of these studies, the genome-wide significance was not achieved (see Laje and McMahon 2011
; Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium 2012
, for recent reviews). This observation most probably means that the genetic research in MDD shall proceed by studying smaller, but clearly defined groups of the patients rather than by sheer increase in overall power of the study. Thus, we believe that our approach to the dissection of IFN-α-induced depression may be worthwhile to replicate for other homogenous groups of MDD patients.
In conclusion, our data demonstrate a significant down-regulation of TGF-β1 and dysregulation of Th1-Th2 cytokine balance in the depression associated with IFN-based treatment of HCV infection. We propose that TGF-β1 may play a role in the imbalance of the Th1/Th2 cytokine ratio in patients with CH-C and depression. With further validation, TGF-β1 and other components of Th1/Th2 regulation pathway may provide a quantitative marker for HCV patients predisposed to treatment-related depression.