Macrophages (M) in most solid tumors exhibit a distinct immunosuppressive phenotype, but the mechanisms that allow tumor microenvironments to "educate" M are incompletely understood. Here, we report that culture supernatants (TSNs) from several types of tumor cell lines can drive monocytes to become immunosuppressive M. Kinetic experiments revealed that soon after exposure to these TSNs, monocytes began to provoke transient proinflammatory responses and then became refractory to subsequent stimulation. Other TSNs that failed to cause such temporary preactivation did not alter M polarization. Consistent with these results, we observed that the monocytes/M in different areas of human tumor samples exhibited distinct activation patterns. Moreover, we found that hyaluronan fragments constitute a common factor produced by various tumors to induce the formation of immunosuppressive M, and also that upregulation of hyaluronan synthase-2 in tumor cells is correlated with the ability of the IntroductionMacrophages (M) are essential components of host defense and act as both antigen presenting cells (APCs) and effector cells. Under the influence of local conditions, they acquire specialized phenotypic characteristics with diverse functional programs. [1][2][3][4] The M1 or classical M are activated by microbial products and interferon (IFN)-␥, and they are capable of efficiently killing microorganisms and tumor cells and eliciting adaptive Th1 immunity. In contrast, M2 M are distinctly activated by anti-inflammatory molecules, such as interleukin (IL)-4 and IL-10, and they express different receptors, have a poor antigen-presenting capacity, and also suppress T-cell responses. 4,5 The M2 cells share an IL-12 low /IL-10 high phenotype and are generally better adapted to remodeling tissues. [5][6][7] M constitute a major component of the leukocyte infiltrate of tumors, and the tumor-associated M (TAM) are derived almost entirely from circulating blood monocytes. 3,8,9 M in normal or inflamed tissues exhibit spontaneous antitumor activity, whereas TAM are polarized M2 cells that suppress antitumor immunity and promote tumor progression. 5,8 Those findings agree with clinical studies showing that a high density of TAM is associated with poor prognosis in most solid tumors. [8][9][10][11] Although the precise underlying mechanisms are not yet clear, it is generally assumed that the tumor microenvironment is a critical determinant of the phenotype of local M. Tumor-derived factors, including IL-10 and transforming growth factor (TGF)-␤1, "educate" the newly recruited monocytes to take on a M2 phenotype and perform a protumoral role. 4,12 In contrast, overexpression or local delivery of IL-12 can reestablish the antitumor activity of M, and in that case a high density of TAM is correlated with a marked reduction in tumor growth. 13,14 Such opposing effects of M on tumor progression indicate that selective modulation of M polarization might serve as a novel strategy for cancer therapy. However, such an approach is hampered by th...

The post-translational modification of histone tails is the principal process controlling epigenetic regulation in eukaryotes. The lysine methylation of histones is dynamically regulated by two distinct classes of enzymes: methyltransferases and demethylases. JMJD5, which plays an important role in cell-cycle progression, circadian rhythms and embryonic cell proliferation, has been shown to be a JmjC-domain-containing histone demethylase with enzymatic activity towards H3K36me2. Here, the crystal structure of human JMJD5 lacking the N-terminal 175 amino-acid residues is reported. The structure showed that the Gln275, Trp310 and Trp414 side chains might block the insertion of methylated lysine into the active centre of JMJD5, suppressing the histone demethylase activity of the truncated JMJD5 construct. A comparison of the structure of JMJD5 with that of FIH, a well characterized protein hydroxylase, revealed that human JMJD5 might function as a protein hydroxylase. The interaction between JMJD5 and the core histone octamer proteins indicated that the histone proteins could be potential substrates for JMJD5.