Richard Bucala M.D., Ph.D.

Professor of Medicine, Pathology, and Epidemiology and Public Health
Rheumatology

Research Activities

We seek to understand the mechanisms by which host immunity converts from a protective response to one producing disease and tissue pathology. A main focus of our efforts is on the cytokine, MIF, which we had cloned from the pituitary gland and discovered to counter-regulate the immunosuppressive actions of glucocorticoids. MIF production is tightly linked to the expression of many autoimmune and inflammatory diseases, and anti-MIF strategies are effective in reducing immunopathology in many experimental models of disease. An important goal for us is to comprehend the emergence of steroid resistance, a clinical problem that seriously restricts the effective treatment of autoimmune diseases such as rheumatoid arthritis.

Our laboratory investigations encompass the biochemical, biological, and genetic characterization of MIF, and we remain focused on understanding MIF's role in physiology and pathology. We have uncovered a unique action for MIF in sustaining ERK1/2 MAP activation, a pathway that impacts on the proliferation and long-term activation of many cell types. Our studies support an important role for MIF in inhibiting p53-dependent growth arrest, which is an action that sustains the pro-inflammatory phenotype of monocytes/macrophages. We have discovered functionally important polymorphisms in the promoter for human MIF that are associated with the severity of immunologic disease such as rheumatoid arthritis, asthma, and scleroderma, and play a role in the inflammatory pathogenesis of malignancies such as prostate cancer.

We have initiated studies of MIF's role in the development of severe malaria. Malarial anemia is the proximate cause of death in almost half of the 2 million deaths that occur annually from this disease. Bone marrow progenitor cells become resistant to the action of erythropoietin during malaria infection, and we have uncovered a molecular pathway by which MIF interferes with erythropoietin signal transduction. We conduct clinical studies at the Macha Mission Hospital in Zambia to study the clinical frequency of different MIF genetic polymorphisms in an effort to understand why severe malaria develops in certain children. Additional studies are underway in Colombia to examine the role of MIF in recurrent Leishmaniasis.

In a separate line of investigation, we study the biology of fibrocytes, a blood-borne cell with inflammatory and fibrogenic properties. We first characterized these cells in studies of wound repair and granuloma formation, and we are exploring the role of these cells in different systemic fibroses.

Selected Publications

Bucala R. 2000. A most interesting factor. Nature 408, 146-147.

Mizue Y, Ghani S, Leng L, McDonald C, Kong P, Baugh J, Lane SJ, Craft J, Nishihira J, Donnelly SC, Zhu Z, Bucala R. 2005. Role for macrophage migration inhibitory factor in asthma. Proc Natl Acad Sci USA. 102, 14410-14415.

McDevitt MA, Xie J, Shanmugasundaram G, Griffith J, Liu A, McDonald C, Thuma P, Gordeuk VR, Metz CN, Mitchell R, Keefer J, David J, Leng L, Bucala R. 2006. A critical role for the host mediator macrophage migration inhibitory factor in the pathogenesis of malarial anemia. J Exp Med 203, 1185-1196.

Shi X, Leng L, Wang T, Wang W, Du X, Li J, McDonald C, Chen Z, Murphy JW, Lolis E, Noble P, Knudson W, Bucala R. 2006. CD44 Is the Signaling Component of the Macrophage Migration Inhibitory Factor-CD74 Receptor Complex. Immunity 25, 595-606.

Bucala R. 2006. MIF and the Genetic Basis of Macrophage Responsiveness. Current Immunol Reviews 2, 217-223.

Bucala R, Donnelly SC. 2007. Macrophage Migration Inhibitory Factor: A Probable Link between Inflammation and Cancer. Immunity 26, 281-285.

Flaster H, Bernhagen J, Calandra T, Bucala R. 2007. The macrophage migration inhibitory factor-glucocorticoid dyad: regulation of inflammation and immunity. Mol Endocrinol 21, 1267-1280.

Arjona A, Foellmer HG, Town T, Leng L, McDonald C, Wang T, Wong SJ, Montgomery RR, Fikrig E, Bucala R. 2007. Abrogation of macrophage migration inhibitory factor decreases West Nile virus lethality by limiting viral neuroinvasion. J Clin Invest 117, 3059-3066.

Atsumi T, Cho YR, Leng L, McDonald C, Yu T, Danton C, Hong EG, Mitchell RA, Metz C, Niwa H, Takeuchi J, Onodera S, Umino T, Yoshioka N, Koike T, Kim JK, Bucala R. 2007. The Pro-inflammatory Cytokine Macrophage Migration Inhibitory Factor Regulates Glucose Metabolism during Systemic Inflammation. J Immunol 179, 5399-5406.

Lab Members

Research Assistants
Marta Piecychna	(203) 737-5103
Courtney McDonald	(203) 737-5103
Research Associates
Juan Fan	(203) 737-5103
Graduate Students
Jason Griffith, BS	(203) 737-5103
Tiffany Sun, BA	(203) 737-5103
Postgraduate Students
Daniela Kamir	(203) 737-5103
Melanie Merk	(203) 737-5103
Postdoctoral Associates/Fellows
Tarah Connolly, Ph.D.	(203) 737-5103
Xin Du, Ph.D.	(203) 737-5103
Research Scientists
Lin Leng, Ph.D.	(203) 737-5103
Visiting Research Faculty
Wen Kui Wang, Ph.D.	(203) 737-5103
Wan-Uk Kim, M.D.	(203) 737-5103
Clinical Fellows
Antoine Sreih, M.D.	(203) 785-7933
Philip Kuo, M.D. PhD.	(203) 508-0075

Contact

Campus Address
300 Cedar Street
TAC S-525C

Mailing Address
Yale University School of Medicine
P.O. Box 208031
New Haven, CT 06520-8031

E-mail
richard.bucala@yale.edu

Office Phone
(203) 785-2453

Fax
(203) 785-7053