Cytokine Receptor Kinetics
|
Cytokine |
k+
(binding)
nM-1 min-1 |
k-
(unbinding)
min-1 |
Kd =
k- / k+
nM |
receptor
sites/cell |
Half-life on surface |
Ref |
|
IL-6 (mouse)
High affin |
|
|
0.2 |
300-720 |
16-30 min |
[1] |
|
IL-6R (mouse) to human IL-6 |
|
|
2.25 |
100-500 |
|
[1] |
|
IL-6 |
0.013 |
0.054 |
4.3 |
|
|
[2] |
|
Human interleukin DA
(high affinity) |
2.4 |
0.0084 |
3.8 x 10-3 |
20 to 600 |
|
[4] |
|
human interleukin DA
(low affinity) |
0.072 |
.18 |
2.6 |
1,000 to 5,000 |
|
[4] |
|
IL-1 alpha
(high aff) |
|
|
.06 |
100 |
1-2 hr |
[5] |
|
IL-1 alpha
(low aff) |
|
|
1 |
900 |
|
[5] |
|
IFN-gamma |
|
|
0.3 |
8000 |
Lower than IL-1alpha |
[5] |
|
IL-1
Human B-lymphoma |
|
|
2.1 |
7709 |
|
[6] |
|
IL-1 murine T-lymphoma |
|
|
0.4 |
241 |
|
[6] |
|
IL-1
Murine thymoma cell |
|
|
0.15 |
|
|
[7] |
|
IL-1 alpha
(low aff) |
|
|
10 |
|
|
[8] |
|
IL-1 alpha
(high aff) |
|
|
0.1 |
|
|
[8] |
|
IL-1 beta |
|
|
1.0 |
|
|
[8] |
|
TNF alpha
(high aff)
rat liver |
|
|
1.5 |
|
|
[9] |
|
TNF alpha
(low aff)
rat liver |
|
|
13.6 |
|
|
[9] |
|
TNF
mouse leukemia |
|
|
Human TNF 1.7- 2.8 nM |
750-1,100 |
15 -95 min |
[10] |
|
TNF
Mouse
leukemia |
|
|
Mouse TNF
0.2-0.7 |
750-1,100 |
|
[10] |
|
TNF-beta
overexpr
Human cells |
|
|
1.1 |
264,000 |
|
[11] |
|
TNF alpha
overexpr
Human cells |
|
|
0.2 |
94,000 |
25 min |
[11] |
|
TNF alpha
Recombi-nant human |
|
|
1.3 |
1100 |
1 h (for 0.6 ng/ml LPS)
15 min (for 10 ng/ml ) |
[12] |
|
IL-1 receptors in rat & mouse |
Regions |
Kd |
Bmax* [fmol/mg protein] |
Ref |
|
IL-1beta (rat) |
Hypothlamus |
1.0(+-)0.2 nM |
75.4(+-)10.8 |
[13] |
|
IL-1beta (rat) |
Cerebral cortex |
1.3(+-)0.2 nM |
17.2(+-)1.5 |
[13] |
|
IL-1beta (rat) |
Lymphocytes or
Fibroblasts |
8 - 200 pM |
|
[13] |
|
IL-1alpha (mouse) |
Hippocampus |
114(+-)35 pM |
2.5(+-)0.4 |
[14] |
*Bmax = maximum binding capacity (see [13]).
Pharmacological specificity of IL-1alpha (100 pM) binding to mouse hippocampus (from [14]).
|
Peptide |
Ki* [pM] |
Potency relative to IL-1alpha |
Biological activity [U*/mg] |
|
IL-1alpha |
55(+-)18 |
1.0 |
3.1 X 107 |
|
IL-1beta |
76(+-)20 |
0.72 |
2.0 X 107 |
|
IL-1beta+ |
2940(+-)742 |
0.02 |
1.0 X 106 |
|
Human TNF |
> 100,000 |
< 0.0006 |
8.0 X 102 |
|
Rat/human CRF |
> 100,000 |
< 0.0006 |
0.0 |
*Ki = inhibitory binding affinity constant (see [14]).
* 1U activity = the amount required for half-maximal induction of cell proliferation (see [14]).
Summary of Calculations
To estimate the rate at which cytokines are absorbed,
the following assumptions and calculations were made:
The density of receptors
Let V be the volume (in cubic microns) of the cell in question.
Let r be the number of receptors per cell.
r (rec/cell) x (1/V) (cell/micron
3) x
(1/6.02 x 10
-23) (Mole/rec)
x (10
12) (micron
3/cm
3) x (10
3)
(cm
3/Litre) x (10
9) (nM/M)
= (r/V) x (1.655) nM
Using the rough dimensions of 10x10x10 microns for an astrocyte,
we estimate the volume of an astrocyte to be
V = 1000 (micron
3).
We used an an estimate of
20,000 neurons in a 1 square mm by 25 micron section. This
turns out to be a volume of 25 x 10
6 micron
3.
Dividing the
total volume by the number of cells gives an estimate of
V = 1250 (micron
3) for neurons.
Rate of cytokine absorption
We use the following as a ballpark figure for the rate of absorption
of a given cytokine by a cell having a particular cytokine
receptor:
(kf*s - kb)(r/2) = (kb*r/2)*[(1/KD)*s - 1]
where
- kf = receptor-ligand binding rate
- kb = receptor-ligand unbinding rate
- KD = equilibrium constant
- s = concentration of ligand (cytokine)
- r = concentration of receptors
Remarks
- According to [13], the IL-1 alpha receptor does NOT bind with IL-1 beta receptors in rat brain. Also, the IL-1 beta receptors in the rat brain are different from those for IL-1 alpha.
- According to [14], in mouse hippocampus, IL-1 alpha showed approximately 24-fold higher specific binding than IL-1 beta.
References
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the IL-6 receptor and gp130 but fails to induce a stable hexameric receptor
complex.Journal of Biological Chemistry. 271(10):5464-73, 1996 Mar 8. Abstract
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- Godard A. Heymann D. Raher S. Anegon I. Peyrat MA. Le
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inhibitory factor on human cells. Molecular characterization and cellular
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Tables of Parameters