title: Epinephrine promotes COX-2-dependent immune suppression in myeloid cells and cancer tissues.
abstract: Activation of the sympathetic nervous system (e.g., due to stress) has been implicated in cancer progression and recurrence, but its cancer-promoting effects have been variable between different studies. Here, we report that although catecholamines, mediators of systemic sympathetic activity, display only weak immunosuppressive impact on their own, their combination with inflammatory signals leads to the induction of COX-2 and multiple COX-2-dependent suppressive factors in human myeloid cells and cancer tissues. Human macrophages exposed to epinephrine and TNFα, or macrophages generated in 6day cultures in the presence of epinephrine, expressed high levels of COX-2, IDO and IL-10, and strongly suppressed both the proliferation and IFNγ production of CD8+T cells. These suppressive effects of epinephrine were counteracted by celecoxib, a selective inhibitor of COX-2 activity, which inhibited the induction of immunosuppressive factors (including the elevated expression of COX-2 itself) and the ability of epinephrine-exposed macrophages to suppress CD8+T cell responses. The activation of the COX-2/PGE2system and COX-2-dependent suppressive events were also observed in ex vivo human breast and colon cancer explant cultures and were similarly counteracted by celecoxib. Our preliminary data also indicate elevated COX-2 expression in mammary tumors of chronic stress-exposed mice. The current demonstration of the interplay between inflammation and the induction of immunosuppressive factors by catecholamines suggest a contextual impact of stress, helping to explain variable results of epidemiologic studies of the link between sympathetic activity and cancer progression, and implicating COX-2 blockade as a potential means to mitigate stress-related immune suppression.
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Muthuswamy
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Nana J
authors.initials: NJ
authors.lastname: Okada
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA; The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Jenkins
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA; The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: Kandace
authors.initials: K
authors.lastname: McGuire
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA; The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: Priscilla F
authors.initials: PF
authors.lastname: McAuliffe
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA; The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Zeh
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA; The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Bartlett
authors.affiliation: Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Callen
authors.initials: C
authors.lastname: Wallace
authors.affiliation: Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Watkins
authors.affiliation: Department of Psychiatry, Psychology and Behavioral & Community Health Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Biology, University of Pittsburgh at Johnstown, Johnstown, PA 15904, USA.
authors.forename: Jill D
authors.initials: JD
authors.lastname: Henning
authors.affiliation: The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA; Department of Psychiatry, Psychology and Behavioral & Community Health Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: bovbjergdh@upmc.edu.
authors.forename: Dana H
authors.initials: DH
authors.lastname: Bovbjerg
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA; The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA; Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: KalinskiP@upmc.edu.
authors.forename: Pawel
authors.initials: P
authors.lastname: Kalinski
mesh_terms: D000818:Animals; D000068579:Celecoxib / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology*; D005260:Female; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016753:Interleukin-10; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D004837:Epinephrine
keywords: Breast cancer; CTLs; Colon cancer; Epinephrine; IDO; Immune suppression; Inflammation; Prostaglandins; Stress; Suppressive macrophages; cAMP