download report - Istituto Pasteur

P a r t i c i p a n t s :
Antonio Filippini, professor; Anna Riccioli, researcher;
Claudia Giampietri, Donatella Starace, post-doc fellows,
Roberta Galli, Alessio Paone, PhD students; Giuseppina
Avigliano, graduate student; Fabrizio Padula, Simonetta
Petrungaro, technicians.
C o l l a b o r a t i o n s :
Dipartimento di Medicina Sperimentale, Università de L’Aquila
(Prof. Paola De Cesaris).
Report of activity
Viruses are known to be capable of infecting the male
reproductive tract resulting, in some instances, in
impaired fertility. In the testis, it is well known that
viruses can induce pathological conditions such as
orchitis, decrease in semen quality and may participate
in the etiology of testicular cancer (Kondho, J Virol.
1991), however the molecular mechanisms involved
are still under investigation. The major role of Sertoli
cells in the antiviral defence system is confirmed by
data showing that they constitutively express several
IFN-induced antiviral proteins, such as 2’5’ A synthetase,
Mx2 and Mx1 proteins and PKR. Toll-like
receptors (TLRs) recognize pathogen-associated
molecular patterns (PAMPs) and elicit antimicrobial
immune responses. We have previously demonstrated
that mouse Sertoli cells play a key role in the bactericidal
testicular defence mechanism by expressing a
panel of TLRs (Riccioli, J Immunol. 2006). In order to
better characterize the potential role of Sertoli cells in
the response against testicular viral infections, we
investigated the presence of TLR3, TLR7, and TLR9
in primary Sertoli cell cultures from young mice. We
observed that Sertoli cells significantly express TLR3
mRNA and protein, whereas TLR7 and TLR9 are not
expressed, as assessed by RT-PCR.
Upon ligand binding, TLR3 interacts with the adaptor
protein, TRIF (Toll/IL1-receptor domain con-
Principal investigator: Elio Ziparo
Professor of Embryology
Dipartimento di Istologia ed Embriologia Medica
Tel.: (+39) 06 49766586; Fax: (+39) 0649766340
elio.ziparo@uniroma1.it
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Cellular and molecular immunology - AREA 5
The role of Toll Like Receptors in immune responses to infections
and in inflammation associated pathologies of the male
reproductive system
taining adapter inducing IFNB1), which mediates
the activation of NF-KB, mitogen activated protein
kinases (MAPKs), and IFN regulatory factor 3
(IRF3) as well as the induction of type I IFNs,
cytokines critical to the host defence against viral
infections. We reported that Sertoli cells, under
stimulation with specific TLR3 agonist, the synthetic
dsRNA analogue poly (I:C), produce the proinflammatory
molecule ICAM-1 and secrete the
functionally active chemokine CCL2. By using both
pharmacological and genetic approaches, we report
that these effects are TLR3-dependent. Moreover,
by using ELISA, we show that IFNA is constitutively
produced and not further inducible, whereas
IFNB is absent but is strongly inducible by poly
(I:C) only if it is transfected into cells. These data
are in agreement with those of previous reports on
different cell types (Milhaud, Bioconjug Chem. 1992)
showing that poly (I:C), either microinjected or
delivered with acid-sensitive liposomes, induces IFN
production. These data indicate different control
mechanisms underlying IFNA and IFNB production.
To conclude, our results demonstrate that poly
(I:C) elicits both inflammatory and antiviral
responses in Sertoli cells.
Since chronic infection and inflammation are strongly
linked with the development and progression of
carcinogenesis, a further topic of this project concerns
the potential role of TLRs within the development
and etiology of prostate cancer, the most common
tumour in the male reproductive tract. So far,
regarding the linkage between TLR activation and
prostate cancer, in addition to epidemiological data
linking chronic inflammation to increased cancer
risk, genetic link between TLR and cancer also
exists. In fact, sequence variants in Tlr gene cluster
(Tlr6–Tlr1–Tlr10) and in Tlr4 are related to
increased risk of human prostate cancer (Sun, J Natl
Cancer Inst. 2005; Chen, Cancer Res. 2005), clearly
indicating a role of TLRs in its aetiology. Such association
of gene sequence variants and prostate can-