Macrophage migration inhibitory factor and CD74 regulate macrophage chemotactic responses via MAPK and Rho GTPase.

نویسندگان

  • Huapeng Fan
  • Pam Hall
  • Leilani L Santos
  • Julia L Gregory
  • Gunter Fingerle-Rowson
  • Richard Bucala
  • Eric F Morand
  • Michael J Hickey
چکیده

Macrophage migration inhibitory factor (MIF) promotes leukocyte recruitment to sites of inflammation. However, whether this stems from a direct effect on leukocyte migration is unknown. Furthermore, the role of the MIF-binding protein CD74 in this response has not been investigated. Therefore, the aim of this study was to examine the contributions of MIF and CD74 to chemokine-induced macrophage recruitment. Intravital microscopy studies demonstrated that CCL2-induced leukocyte adhesion and transmigration were reduced in MIF(-/-) and CD74(-/-) mice. MIF(-/-) and CD74(-/-) macrophages also exhibited reduced chemotaxis in vitro, although CD74(-/-) macrophages showed increased chemokinesis. Reduced CCL2-induced migration was associated with attenuated MAPK phosphorylation, RhoA GTPase activity, and actin polymerization in MIF(-/-) and CD74(-/-) macrophages. Furthermore, in MIF(-/-) macrophages, MAPK phosphatase-1 was expressed at elevated levels, providing a potential mechanism for the reduction in MAPK phosphorylation in MIF-deficient cells. No increase in MAPK phosphatase-1 expression was observed in CD74(-/-) macrophages. In in vivo experiments assessing the link between MIF and CD74, combined administration of MIF and CCL2 increased leukocyte adhesion in both MIF(-/-) and CD74(-/-) mice, showing that CD74 was not required for this MIF-induced response. Additionally, although leukocyte recruitment induced by administration of MIF alone was reduced in CD74(-/-) mice, consistent with a role for CD74 in leukocyte recruitment induced by MIF, MIF-treated CD74(-/-) mice displayed residual leukocyte recruitment. These data demonstrate that MIF and CD74 play previously unappreciated roles in CCL2-induced macrophage adhesion and migration, and they indicate that MIF and CD74 mediate this effect via both common and independent mechanisms.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

I-43: Expression Profile of Macrophage Migration Inhibitory Factor (MIF) Signaling Pathway as A Potentional Biomarker in Pathophysiology of Endometriosis

Background MIF via its receptor, CD74, initiates a signaling cascade that leads to proliferation and survival of cells. Also, MIF binding to CD74 activates p38 signaling pathways that lead to positive effect on the expression of COX-2. The aim of this study was to evaluate the gene expression profile of MIF, CD74 and COX-2 in normal, ectopic and eutopic endometrium during menstrual cycle. The e...

متن کامل

O-28: Endometriosis Is Influenced by The Promoter Haplotype-Based Expression of Macrophage Migration Inhibitory Factor (MIF)

Background: Macrophage migration inhibitory factor (MIF) is a key pro-inflammatory cytokine that is secreted by accumulated active macrophages in ectopic tissue of endometriosis. MIF is involved in pathophysiological events of endometriosis, such as angiogenesis and cell proliferation. MIF that stimulates the synthesis of PGE2, leads to over-expression of local estradiol synthesis in endometrio...

متن کامل

β-Arrestin1 Mediates the Endocytosis and Functions of Macrophage Migration Inhibitory Factor

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine, regulating inflammatory and immune responses. MIF binds to cell surface receptor CD74, resulting in both rapid and sustained ERK activation. It was reported that MIF-induced rapid ERK activation requires its co-receptor CD44. But the exact mechanism underlying sustained ERK activation is not well understood. In the current ...

متن کامل

Macrophage migration inhibitory factor activates inflammatory responses of astrocytes through interaction with CD74 receptor

Astrocytes, the major glial cell population of the central nervous system (CNS), play important physiological roles related to CNS homeostasis. Growing evidence demonstrates that astrocytes trigger innate immune responses under challenge of a variety of proinflammatory cytokines. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine mainly secreted from monocytes/macrophages,...

متن کامل

PAK1-mediated activation of ERK1/2 regulates lamellipodial dynamics.

PAK1 is a member of the p21-activated kinase (PAK) family of serine/threonine kinases that are activated by the Rho GTPases Rac and Cdc42, and are implicated in regulating morphological polarity, cell migration and adhesion. Here we investigate the function of PAK1 in cell motility using macrophages derived from PAK1-null mice. We show that CSF1, a macrophage chemoattractant, transiently stimul...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Journal of immunology

دوره 186 8  شماره 

صفحات  -

تاریخ انتشار 2011