IL-32, a potential therapeutic target for rheumatoid arthritis?

Abstract

Recently, we read with great interest the article, published in Rheumatol Int, showing that IL-32 injected into knee joints of CIA mice induced elevated scores of synovial inflammation, bone destruction, synovial expressions of IL1b, TNF-a, IL-18 and IFN-c [1]. Furthermore, synovial expressions of NK cell, chemokines (CCL2 and CXCL9) and chemokine receptors (CCR2 and CCR5) were markedly increased in IL-32-treated CIA mice [1]. These findings suggest that IL-32 may play an important role in the pathogenesis of rheumatoid arthritis (RA), and IL-32 may be a therapeutic target in RA. IL-32 is a multifunctional cytokine generated by T lymphocytes, NK cells, monocytes and epithelial cells. There are six isoforms of IL-32, including IL-32a, IL-32b, IL-32c, IL-32d, IL-32e and IL-32f [2]. It has been found that serum, peripheral blood mononuclear cells (PBMCs) of RA patients had increased levels of IL-32, respectively [3, 4]. Furthermore, IL-32 was highly expressed in RA synovial tissue [5–7], and IL-32 was correlated with the expression of IL-6, TNFa, IL-1b and IL-18 [5, 7]. Peritoneal macrophages collected from C3H/HeJ mice cultured with human IL-32 induced the synthesis of TNFa and IL-1b, as that of the chemokine macrophage inflammatory protein 2 (MIP-2) [7]. Similarly, human IL-32 stimulated the generation of prostaglandin E2 (PGE2) by human PBMC, an important mediator of cartilage and bone destruction in RA [7]. IL-32a transgenic mice found high levels of IL-32a mRNA expression in a variety of organs prominently in the knee joint and cardiac muscle and overexpressed IL-32a-induced constitutive expression of TNFa mRNA in colon and knee joints [8]. CD4? T cells transduced the hIL-32b gene, and then, these cells transferred to bovine type II collagen-immunized mice before the onset of arthritis. Shoda et al. [4] found that this group of mice developed arthritis earlier than the mock group of mice and showed significantly higher arthritis scores. Histological investigation of the joints showed severe cell infiltration in the hIL-32b group of mice [4]. Intra-articular injection of AdIL-32c (IL-32c mRNA derived from an adenoviral vector) into mouse knee joints resulted in markedly enhanced joint swelling, and histological analysis showed enhanced synovial infiltrating cells in the joints [5]. In synovial tissue, mRNA expression of TNFa, IL-1b, and IL-6 was significantly elevated in AdIL-32c-exposed joints [5]. It has also been found that AdIL-32c-transduced human FLS (fibroblast-like synoviocytes) increased CXCL8, IL-1b, CCL20, MMP1 and MMP3 mRNA expression [9]. On the contrary, silenced intracellular IL32c expression in FLS cells led to significant suppression of IL-6 and CXCL8 production [9]. FLS from RA patients stimulated with TNFa enhanced IL-32 expression, but the PKCd inhibitor rottlerin and the JNK inhibitor SP600125 suppressed TNFa-induced IL-32 expression in the cells [6]. Transfection with siRNA targeted against PKCd, JNK led to the suppression of expression of IL-32 as well [6]. Q. Xie C. Huang J. Zhong W.-W. Shen J. Li (&) School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui, People’s Republic of China e-mail: lj@ahmu.edu.cn