Immunologic Research

, Volume 66, Issue 2, pp 245–254 | Cite as

The human breast cancer-associated protein, the prolactin-inducible protein (PIP), regulates intracellular signaling events and cytokine production by macrophages

  • Olivia Ihedioha
  • Anne A. Blanchard
  • Jyoti Balhara
  • Ifeoma Okwor
  • Ping Jia
  • Jude Uzonna
  • Yvonne Myal
Original Article

Abstract

The prolactin-inducible protein (PIP) is considered a valuable biomarker that is associated with both benign and malignant pathological conditions of the mammary gland. The function of PIP in breast tumorigenesis remains unknown; however, evidence from our laboratory and others suggest that it regulates host immunity. Studies with PIP-deficient (PIP−/−) mice demonstrated significantly lower numbers of CD4+ T cells in their secondary lymphoid organs, impaired Th1 response, and impaired nitric oxide (NO) production. To further delineate the immunoregulatory role of PIP, we compared the expression of IFN-γR and TLR4, pro-inflammatory cytokine production, and intracellular signaling events by IFN-γ and lipopolysaccharide (LPS)-stimulated macrophages from wild-type (WT) and PIP−/− mice. We showed that although the expressions of IFN-γR and TLR4 were comparable, productions of pro-inflammatory cytokines were decreased in PIP−/− macrophages. This was associated with decreased phosphorylation of mitogen-activated protein kinase (MAPK) and signal transducer of activation of transcription (STAT) proteins in macrophages from PIP−/− mice. Interestingly, the expression of suppressors of cytokine signaling (SOCS) 1 and 3 proteins, known to suppress IFN-γ and LPS signaling, was higher in PIP−/− macrophages compared to those from WT mice. Collectively, our studies show that deficiency of PIP significantly affects intracellular signaling events leading to decreased pro-inflammatory cytokine production, and further confirms a role for PIP as an important immunoregulatory protein. This direct link between PIP and cell-mediated immunity, a key component of the immune system that is critical for cancer control, may have significant therapeutic implications.

Keywords

Prolactin-inducible protein Macrophages Lipopolysaccharide Interferon gamma Cell-mediated immunity Breast cancer 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

The University of Manitoba Animal Care and Use Committee approved this project. All the mice used were maintained at the Central Animal Care Services under specific pathogen-free conditions and used according to guidelines stipulated by the Canadian Council for Animal Care.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PathologyUniversity of ManitobaWinnipegCanada
  2. 2.Department of Physiology and PathophysiologyUniversity of ManitobaWinnipegCanada
  3. 3.Department of ImmunologyUniversity of ManitobaWinnipegCanada
  4. 4.Department of Medicine, Faculty of Health SciencesMcMaster UniversityHamiltonCanada

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