The polarization of Th1/Th2 balance is dependent on the intracellular thiol redox status of macrophages due to the distinctive cytokine production

Abstract

We have been proposing the functional discrimination of two classes of macrophages (Mp), i.e. reductive macrophages (RMp) with a high intracellular content of glutathione and oxidative macrophages (OMp) with a reduced content. In this paper we will present the evidence that theT_h1/T_h2 balance is regulated by the balance between RMp and OMp due to the disparate production of IL-12 versus IL-6 and IL-10. RMp were induced by in vivoapplication of N-acetyl-L-cysteine or glutathione monoethylester and OMp by L-cystine derivatives, diethyl maleate or L-buthionine-[S,R]-sulfoximine. The Mp arbitrarily called OMp showed elevated IL-6 and IL-10 production, and reduced NO and IL-12 production. The RMp elicited a reciprocal response, i.e. elevated IL-12 and NO production, and reduced IL-6 and IL-10 production. The cytokine propensities of OMp or RMp were inter-converted to each other. The results were also confirmed by using auto-MACS purifiedF4/80⁺ Mp without adherence. Interestingly, IFN-γ induced RMp and augmented NO generation with decreased production of IL-6, whilst IL-4 induced OMp and augmented IL-6 production. CD4⁺CD44⁻ naive T_h0 cells were differentiated preferentially either to T_hl or T_h2 cells, depending on the presence of RMp or OMp during the initial 24 h of culture, from ovalbumin-specific TCR-transgenic mouse spleen cells in the presence of IL-2. Taken together, RMp induction may generate the amplification loop of a RMp/T_h1 circuit and OMp that of OMp/T_h2. The findings implicate that the alteration in Mp functions because altered intracellular glutathione may play a relevant role in the pathological progression of inflammation.