Biology Reference
In-Depth Information
As discussed earlier, most if not all tissues express TLRs. Therefore, if a higher
regulatory system, such as the CNS, is injured or paralyzed, for instance, TLR could
still signal the system through lower circuits such as the pituitary, adrenals, thyroid,
and gonads and thus stimulate host resistance. TLR signaling is also possible at the
CTK or even at the cellular level, as all leukocytes express TLR. Thus, even exten-
sive injury to the host organism cannot prevent the INIM system from providing a
defense, as TLR could directly signal the immunocytes to respond and they would
respond with the function they normally perform. For instance, LPS, which activates
TLR4, stimulates natural antibody formation, and is able to stimulate many other
systems, including the CNS
[22]
. The wide spectrum of cells, tissues, and organs
that are stimulated by LPS
in vivo
indicate the extent to which the NISS can be acti-
vated by TLR4. Is it possible that during acute illness TLR, or rather INIRs, are able
to substitute for regulation by the CNS and in this way promote host defense under
circumstances in which the central regulatory system has failed to do so? Indeed,
LPS may be used as an immunological adjuvant, and detoxified LPS was found to
significantly increase survival in lethally injured animals and patients with severe
disease
[64]
.
The CTK response by the INIM system, in rats stimulated with complete Freund's
adjuvant and brain tissue (to induce experimental autoimmune encephalitis (EAE),
was not eliminated by anterior pituitary lobectomy (AL), neurointermediate and pos-
terior lobectomy (NIL), or Hypox, although significant changes were seen in the CTK
response. AL rats showed significant elevation of IL-1, -2, -6, and -10, whereas NIL
animals had the lowest levels of IL-1, -2, -10, -12, and IFN. These results showed that
lack of the HPA axis leads to increased CTK production, whereas the intermediate/
posterior lobe appeared to be stimulatory for the CTK response. On this basis and
that of previous experiments
[28]
, we assumed that VP stimulates the CTK response.
However, in Hypox animals CTK levels remained normal in all experimental groups
examined. We explain this finding by the activation of lower regulatory circuits.
For example, if pituitary hormones are removed completely from the animal, CTK
levels are maintained at normal levels by other regulatory circuits, which could be
neurotransmitter-peptide circuits, stimulatory and inhibitory CTK circuits, or even
cell-to-cell regulation. It should be noted that macrophage numbers in the spleen were
proportional to the levels of CTKs in the serum
[63]
.
Elenkov and colleagues lesioned the PVN in rats and observed that such rats
responded to LPS. Evidence was obtained that 4 hours after treatment, LPS was able
to activate the hypophysial-adrenal system in the absence of hypophysiotrophic neuro-
peptides of paraventricular origin. It was suggested that,
in vivo
, LPS could have a direct
effect on the pituitary gland or that it acts through a nonparaventricular pathway to acti-
vate the HPA axis
[65]
.
These experiments show that elimination of the PVN does not stop the INIM sys-
tem from responding, either. The PVN is the center of regulation for ADIM function.
However, in this case LPS can act directly on TLR4 of the pituitary gland: thus, the
HPA axis is still activated, in spite of the regulatory handicap, and GCs can exert
their all-important moderating/suppressing action on excess CTK production during
endotoxin shock
[29]
.
