Endotoxin-induced cytokine and chemokine expression in the HIV-1 transgenic rat.
BACKGROUND
Repeated exposure to a low dose of a bacterial endotoxin such as lipopolysaccharide (LPS) causes immune cells to become refractory to a subsequent endotoxin challenge, a phenomenon known as endotoxin tolerance (ET). During ET, there is an imbalance in pro- and anti-inflammatory cytokine and chemokine production, leading to a dysregulated immune response. HIV-1 viral proteins are known to have an adverse effect on the immune system. However, the effects of HIV-1 viral proteins during ET have not been investigated.


METHODS
In this study, HIV-1 transgenic (HIV-1Tg) rats and control F344 rats (n = 12 ea) were randomly treated with 2 non-pyrogenic doses of LPS (LL) to induce ET, or saline (SS), followed by a high challenge dose of LPS (LL+L, SS+L) or saline (LL+S, SS+S). The gene expression of 84 cytokines, chemokines, and their receptors in the brain and spleen was examined by relative quantitative PCR using a PCR array, and protein levels in the brain, spleen, and serum of 7 of these 84 genes was determined using an electrochemiluminescent assay.


RESULTS
In the spleen, there was an increase in key pro-inflammatory (IL1α, IL-1β, IFN-γ) and anti-inflammatory (IL-10) cytokines, and inflammatory chemokines (Ccl2, Ccl7, and Ccl9,) in response to LPS in the SS+L and LL+L (ET) groups of both the HIV-1Tg and F344 rats, but was greater in the HIV-1Tg rats than in the F344. In the ET HIV-1Tg and F344 (LL+L) rats in the spleen, the LPS-induced increase in pro-inflammatory cytokines was diminished and that of the anti-inflammatory cytokine was enhanced compared to the SS+L group rats. In the brain, IL-1β, as well as the Ccl2, Ccl3, and Ccl7 chemokines were increased to a greater extent in the HIV-1Tg rats compared to the F344; whereas Cxcl1, Cxcl10, and Cxcl11 were increased to a greater extent in the F344 rats compared to the HIV-1Tg rats in the LL+L and SS+L groups.


CONCLUSIONS
Our data indicate that the continuous presence of HIV-1 viral proteins can have tissue-dependent effects on endotoxin-induced cytokine and chemokine expression in the ET state.
Institute of NeuroImmune Pharmacology, Seton Hall University, South Orange, NJ 07079, USA.
Natasha F
NF
Homji
Xin
X
Mao
Erik F
EF
Langsdorf
Sulie L
SL
Chang
D000704:Analysis of Variance; D000818:Animals; D018925:Chemokines / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004731:Endotoxins / Q000494:pharmacology*; D015497:HIV-1 / Q000235:genetics*; D011134:Polysaccharides / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D013154:Spleen / Q000187:drug effects / Q000201:enzymology
D018925:Chemokines; D016207:Cytokines; D004731:Endotoxins; D011134:Polysaccharides