ReviewThe two faces of IL-6 on Th1/Th2 differentiation
Introduction
Activation of naı̈ve CD4+ helper T (Th) cells through the TcR causes these cells to proliferate and differentiate into effector T helper cells. Two major subsets of effector Th cells have been defined on the basis of their distinct cytokine secretion patterns and their immunomodulatory effects. Th1 cells produce primarily interferon-gamma (IFNγ) and tumor necrosis factor β (TNFβ), which are required for cell-mediated inflammatory reactions; Th2 cells secrete interleukin (IL)-4, IL-5, IL-10 and IL-13, which mediate B cell activation and antibody production (for review, see Swain, 1995, O’Garra, 1998, Murphy et al., 2000). In general, an efficient clearance of intracellular pathogens is based on innate cell activation, while antibody responses are best suited for extracellular infections. The decision of naı̈ve CD4+ T cells to become Th1 and Th2 has important consequences in the success of an immune response and the progression of diseases. A Th1 response against Leishmania major results in the resolution of disease, while a Th2-type response allows the progression of disease. In contrast, a predominant Th1 response has been observed in several autoimmune diseases, such as rheumatoid arthritis, experimental autoimmune encephalomyelitis (EAE) and insulin-dependent diabetes mellitus.
The selective differentiation of precursor CD4+ T cells into effector Th1 and Th2 cells is established during the initial priming of these cells and is influenced by a variety of extracellular factors, such as the cytokine environment, the dose of antigen and the source of costimulation (Constant and Bottomly, 1997). Among these, the most effective polarizing factor is the cytokine environment. The presence of IL-4 during activation drives the differentiation of precursor CD4+ T cells into Th2 cells, whereas the presence of IL-12, IL-18 and IFNγ promotes differentiation into Th1 cells (Hsieh et al., 1993, Le Gros et al., 1990, Nakanishi et al., 2001, Seder et al., 1993, Swain et al., 1990). While IL-12 is secreted by professional antigen presenting cells (APCs), IL-4 is not.
IL-6 is a cytokine produced by a number of cell types including fibroblasts, macrophages, dendritic cells, T and B lymphocytes, endothelial cells, glial cells and keratinocytes in response to a variety of external stimuli (e.g. IL-1, TNF, and PDGF). IL-6 induces the synthesis of acute phase response proteins in hepatocytes, terminal differentiation of B cells to antibody producing plasma cells, differentiation of monocytes to macrophages, and growth of hematopoetic stem cells (for review see Hirano, 1998). IL-6 binds to the surface IL-6 receptor (IL-6R)α, leading to the dimerization of gp130/IL-6Rβ (Taga et al., 1989). Dimerization of gp130 by IL-6 causes the activation of two signaling pathways: (1) the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway; and (2) the CCAAT/enhancer binding protein (C/EBP) pathway. Activation of the extracellular signal-regulated kinase (ERK) pathway by IL-6 appears to mediate phosphorylation and activation of C/EBPβ (NF-IL6; Akira et al., 1990, Daeipour et al., 1993, Poli et al., 1990). IL-6 also induces the expression of C/EBPδ (NF-IL6β), another member of the C/EBP family of transcription factors (Ramji et al., 1993). C/EBPδ together with C/EBPβ regulate Type-1 IL-6 responsive genes (Kinoshita et al., 1992, Poli, 1998). Activation of Jak1, 2, and Tyk2 by IL-6 results in the phosphorylation and activation of STAT3 and, to a much lesser extent, STAT1, leading to the induction of Type-2 IL-6 responsive gene expression (Akira et al., 1994, Lutticken et al., 1994, Nakajima et al., 1995, Stahl et al., 1994).
The production of IL-6 by both lymphoid and non-lymphoid cells makes this cytokine relevant for different aspects of the immune response. Here, we describe the regulatory role of IL-6 on the decision of CD4+ T cells to become Th1 or Th2 effector cells.
Section snippets
IL-6 promotes Th2 differentiation by inducing the expression of IL-4 gene during activation of CD4+ T cells
To test a potential involvement of IL-6 in Th1/Th2 differentiation we examined the effect of IL-6 on IL-4-induced Th2 differentiation or IL-12-induced Th1 differentiation. Interestingly, even in the absence of any polarizing cytokine, IL-6 directed the differentiation of the CD4+ cells to a Th2 phenotype, since the cells differentiated in the presence of IL-6 produce high amounts of IL-4, but not IFNγ, after restimulation (Rincón et al., 1997). IL-6 did not modify the differentiation of the Th2
IL-6 inhibits Th1 differentiation by inducing the expression of SOCS-1 and IFNγ during the activation of CD4+ T cells
We have previously observed that the presence of IL-6 during the differentiation of CD4+ T cells with ConA, APC and IL-12 caused a dramatic inhibition of IFNγ production after restimulation (Rincón et al., 1997). IL-6 also inhibited Th1 differentiation induced with anti-CD3 and IL-12 (Diehl et al., 2002). We also tested whether IL-6 could prevent the differentiation of naı̈ve CD4+ T cells into effector Th1 cells. CD4+ T cells from cytochrome c TcR transgenic mice were unable to differentiate
Conclusive remarks and future directions
Our studies clearly show that IL-6 produced by APCs can modulate the differentiation of CD4+ T cells into effector Th1 or Th2. The presence of IL-6 shifted the Th1/Th2 balance toward the Th2 direction using two independent approaches: (1) promoting IL-4 production and Th2 differentiation; and (2) inhibiting IFNγ production and Th1 differentiation (Fig. 3). While differentiation of Th2 by IL-6 is dependent on endogenous production of IL-4, inhibition of Th1 differentiation by IL-6 is not. IL-6
Acknowledgements
Support for the studies performed in this laboratory was received by the National Institute of Health (PO1 AI45666), the COBRE Program of the National Center for Research Resources (P20 RR15557), the Arthritis Foundation, and the Gustavus and Louise Pfeiffer Foundation. S.D. is supported by an Environmental Pathology Training Grant from the National Institute of Environmental Health Science (T32ES07122).
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