217
ligands of either Toll-like receptors or Fas, as well as phagocytosis by macrophages
[ 75 , 76 ], whereas the content of PrP in monocytes is modulated by IFN-γ [ 77 ].
Additionally, PrP is expressed on the surface of human and mouse mast cells and is
constantly released. A rapid release by mast cells upon activation can be detected.
More importantly, PrP is also released in vivo in responding to mast cell-dependent
allergic inflammation. Although PrP release is activated upon activation, PrP expres-
sion is not required for mast cell differentiation [ 78 ]. When treated with dextran
sodium sulfate, PrP null mice showed elevated BAD protein level, IL-1β, IL-6,
TNF-α, IL-4, IFN-γ, and other cytokine profile to favor inflammation [ 79 , 80 ]. All
these evidences suggest that PrP plays a role in modulating inflammation response.
However, whether to suppress or to activate inflammation reactions probably
depends on the agents or the time of the challenge. Neutrophils play critical roles in
both acute and chronic inflammatory responses. To investigate the role PrP plays in
neutrophil, Mariante et al. injected LPS intraperitoneally into mice and detected a
dose- and time-dependent upregulation of PrP expression. This elevated PrP expres-
sion depends on the serum content of TGFß and glucocorticoids, which, in turn, are
contingent on the activation of the hypothalamic-pituitary-adrenal axis in response
to systemic inflammation [ 81 ]. These results suggest that PrP participates in inflam-
mation, but its physiological functions remain unanswered. Besides participation in
peripheral immune system, PrP also played a role in immune reaction in central
nervous system (CNS). When infected with Mycobacterium bovis, BV2 microglia
cells showed a gradual increase in PRNP mRNA level along with an upregulation of
pro-inflammatory factors. When PrP expression level is silenced by siRNA in M.
bovis-infected BV2 microglia, a reduction of those pro-inflammatory cytokines was
observed. As a consequence, increased apoptosis occurred in infected microglia.
This result implies that microglia PrP is pro-inflammatory when infected by M.
bovis [ 82 ]. In addition to microglia cells, neuron cells expressing PrP also respond
to cytokine treatment. When hippocampal neuron was treated with pro- inflammatory
cytokines TNFα, IL-6, and IL-1ß, neuron cells expressing PrP were induced to form
cofilin/actin (1:1) rods, whereas PrP null neuron cells do not respond to those pro-
inflammatory cytokines. It is worth noting that overexpression of PrP by itself is
sufficient to induce this type of rod in an NOX-dependent manner [ 83 ]. Since
cofilin/actin (1:1) rods have been shown to impair transport and synaptic function of
neuron, an adverse effect of PrP responding to pro-inflammatory reaction in CNS is
anticipated. The function of PrP in vivo was additionally proved in an experimental
autoimmune encephalomyelitis (EAE) mouse model in which EAE is induced by
tail base subcutaneous injection with myelin oligodendrocyte glycoprotein; higher
levels of leukocytic infiltrates and pro-inflammatory cytokine gene expression as
well as increased spinal cord myelin basic protein and axonal loss were detected in
the prnp null spinal cord, cerebellum, and forebrain examined during the acute
phase. In addition, during the chronic phase, a remarkable persistence of leukocytic
infiltrates was present in the forebrain and cerebellum, accompanied by an increase
in interferon-γ and IL-17 transcripts [ 84 ]. Other than bacteria and cytokine treat-
ments, PrP also responds to virus infection in vivo. When infected with 600 pfu
encephalomyocarditis virus B variant (EMCV-B) via an intracranial route, Prnp
13 Prion Protein Exacerbates Tumorigenesis