Background Type II activation of macrophages is known to support Th2 responses development; however, the role of Th2 cytokines (esp. IL-4) on type II activation is unknown. To assess whether the central Th2 cytokine IL-4 can alter type II activation of macrophages, we compared the ability of bone marrow-derived macrophages from wild type (WT) and IL-4Rα-deficient mice to be classically or type II-activated in vitro. Results We found that although both WT and IL-4Rα-deficient macrophages could be classically activated by LPS or type II activated by immune complexes plus LPS, IL-4Rα-deficient macrophages consistently produced much higher levels of IL-12p40 and IL-10 than WT macrophages. Additionally, we discovered that type II macrophages from both strains were capable of producing IL-4; however, this IL-4 was not responsible for the reduced IL-12p40 and IL-10 levels produced by WT mice. Instead, we found that derivation culture conditions (GM-CSF plus IL-3 versus M-CSF) could explain the different responses of BALB/c and IL-4Rα？/？ macrophages, and these cytokines shaped the ensuing macrophage such that GM-CSF plus IL-3 promoted more IL-12 and IL-4 while M-CSF led to higher IL-10 production. Finally, we found that enhanced IL-4 production is characteristic of the type II activation state as other type II-activating products showed similar results. Conclusions Taken together, these results implicate type II activated macrophages as an important innate immune source of IL-4 that may play an important role in shaping adaptive immune responses.
References
[1]
Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8: 958–969.
[2]
Dobrovolskaia MA, Vogel SN (2002) Toll receptors, CD14, and macrophage activation and deactivation by LPS. Microbes Infect 4: 903–914.
[3]
Tierney JB, Kharkrang M, La Flamme AC (2009) Type II-activated macrophages suppress the development of experimental autoimmune encephalomyelitis. Immunol Cell Biol. 87: 235–40.
[4]
Ding AH, Nathan CF, Stuehr DJ (1988) Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. J Immunol 141: 2407–2412.
[5]
Sutterwala FS, Noel GJ, Salgame P, Mosser DM (1998) Reversal of proinflammatory responses by ligating the macrophage Fcgamma receptor type I. J Exp Med. 188: 217–222.
[6]
Edwards JP, Zhang X, Frauwirth KA, Mosser DM (2006) Biochemical and functional characterization of three activated macrophage populations. J Leukoc Biol 80: 1298–1307.
[7]
Anderson CF, Mosser DM (2002) Cutting edge: biasing immune responses by directing antigen to macrophage Fc gamma receptors. J Immunol 168: 3697–3701.
[8]
La Flamme AC, Harvie M, McNeill A, Goldsack L, Tierney JB, et al. (2006) Fcgamma receptor-ligating complexes improve the course of experimental autoimmune encephalomyelitis by enhancing basal Th2 responses. Immunol Cell Biol 84: 522–529.
[9]
Mukherjee S, Chen LY, Papadimos TJ, Huang S, Zuraw BL, et al. (2009) Lipopolysaccharide-driven Th2 cytokine production in macrophages is regulated by both MyD88 and TRAM. J Biol Chem 284: 29391–29398.
[10]
Kang CM, Jang AS, Ahn MH, Shin JA, Kim JH, et al. (2005) Interleukin-25 and interleukin-13 production by alveolar macrophages in response to particles. Am J Respir Cell Mol Biol 33: 290–296.
[11]
Hu-Li J, Pannetier C, Guo L, Lohning M, Gu H, et al. (2001) Regulation of expression of IL-4 alleles: analysis using a chimeric GFP/IL-4 gene. Immunity 14: 1–11.
[12]
Bonder CS, Finlay-Jones JJ, Hart PH (1999) Interleukin-4 regulation of human monocyte and macrophage interleukin-10 and interleukin-12 production. Role of a functional interleukin-2 receptor gamma-chain. Immunology 96: 529–536.
[13]
Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3: 23–35.
[14]
Kuroda E, Ho V, Ruschmann J, Antignano F, Hamilton M, et al. (2009) SHIP represses the generation of IL-3-induced M2 macrophages by inhibiting IL-4 production from basophils. J Immunol 183: 3652–3660.
[15]
La Flamme AC, K Canagasabey, M Harvie, B. T B？ckstr？m (2004) Schistosomiasis protects against multiple sclerosis. Mem Inst Oswaldo Cruz 99: 33–36.
[16]
Weber MS, Prod’homme T, Youssef S, Dunn SE, Rundle CD, et al. (2007) Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat Med 13: 935–943.
[17]
Kim HJ, Ifergan I, Antel JP, Seguin R, Duddy M, et al. (2004) Type 2 monocyte and microglia differentiation mediated by glatiramer acetate therapy in patients with multiple sclerosis. J Immunol 172: 7144–7153.
[18]
Aharoni R, Meshorer A, Sela M, Arnon R (2002) Oral treatment of mice with copolymer 1 (glatiramer acetate) results in the accumulation of specific Th2 cells in the central nervous system. J Neuroimmunol 126: 58–68.
[19]
Ponomarev ED, Maresz K, Tan Y, Dittel BN (2007) CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J Neurosci 27: 10714–10721.
[20]
Grzych JM, Pearce E, Cheever A, Caulada ZA, Caspar P, et al. (1991) Egg deposition is the major stimulus for the production of Th2 cytokines in murine schistosomiasis mansoni. J Immunol 146: 1322–1327.
[21]
Crume KP, Miller JH, La Flamme AC (2007) Peloruside A, an antimitotic agent, specifically decreases tumor necrosis factor-alpha production by lipopolysaccharide-stimulated murine macrophages. Exp Biol Med 232: 607–613.
[22]
Boros DL, Warren KS (1970) Delayed hypersensitivity-type granuloma formation and dermal reaction induced and elicited by a soluble factor isolated from Schistosoma mansoni eggs. J Exp Med 132: 488–507.
