MIF homologues from a filarial nematode parasite synergize with IL-4 to induce alternative activation of host macrophages

Macrophage migration inhibitory factor (MIF) is a highly conserved cytokine considered to exert wide-ranging, proinflammatory effects on the immune system. Recently, members of this gene family have been discovered in a number of invertebrate species, including parasitic helminths. However, chronic helminth infections are typically associated with a Th2-dominated, counter-inflammatory phenotype, in which alternatively activated macrophages (AAMs) are prominent. To resolve this apparent paradox, we have analyzed the activity of two helminth MIF homologues from the filarial nematode Brugia malayi, in comparison with the canonical MIF from the mouse. We report that murine MIF (mMIF) and Brugia MIF proteins induce broadly similar effects on bone marrow-derived mouse macrophages, eliciting a measured release of proinflammatory cytokines. In parallel, MIF was found to induce up-regulation of IL-4R on macrophages, which when treated in vitro with MIF in combination with IL-4, expressed markers of alternative activation [arginase, resistin-like molecule alpha (RELM-alpha) or found in inflammatory zone 1, Ym-1, murine macrophage mannose receptor] and differentiated into functional AAMs with in vitro-suppressive ability. Consistent with this finding, repeated in vivo administration of Brugia MIF induced expression of alternative macrophage activation markers. As mMIF did not induce RELM-alpha or Ym-1 in vivo, alternative activation may require components of the adaptive immune response to Brugia MIF, such as the production of IL-4. Hence, MIF may accentuate macrophage activation according to the polarity of the environment, thus promoting AAM differentiation in the presence of IL-4-inducing parasitic helminths.